Atrazine, Simazine and Cyanazine; Notice of Initiation of Special Review
Federal RegisterNov 23, 1994
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-30000-60; FRL-4919-5]
Atrazine, Simazine and Cyanazine; Notice of Initiation of Special
Review
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of Initiation of Special Review.
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SUMMARY: This notice announces that EPA is initiating a Special Review
on pesticide products containing the herbicides atrazine, simazine and
cyanazine. Atrazine [2-chloro-4-(ethylamino)-6-(isopropylamino)-s-
triazine], simazine [2-chloro-4,6-bis(ethylamino)-s-triazine] and
cyanazine [2-((4-chloro-6-(ethylamino)-s-triazine-2-yl)amino)-2-
methylpropionitrile] will be collectively referred to hereafter in this
Notice as the triazines. The triazines are widely used herbicides that
control many broadleaf weeds and some grasses. All three are used on
corn and may be alternatives for each other in some situations. Other
uses include citrus, nut orchards (simazine), sugarcane and sorghum
(atrazine) and cotton (cyanazine). Based on laboratory animal data, EPA
has concluded that these three triazine compounds are possible human
carcinogens and has determined that exposure to the triazines in the
diet (food and drinking water) may pose risks of concern. EPA has also
determined that exposure to these triazines may pose risks of concern
to applicators and mixer/loaders who use products containing one or
more of these chemicals and to the public who may use home lawncare
products containing atrazine. Accordingly, the Agency has concluded
that products containing atrazine, simazine and cyanazine meet or
exceed the criteria for initiation of Special Review set forth in 40
CFR 154.7(a)(2) and that a Special Review of these products is
appropriate to determine whether additional regulatory actions are
required.
The Agency is concerned about the potential ecological impacts of
ground and surface water contamination resulting from the use of
products containing the triazines. Such contamination may have the
potential to cause adverse effects to aquatic organisms, terrestrial
plants and their ecosystems. The Agency is not including ecological
effects as a trigger in this Special Review at this time. This does not
preclude the Agency from incorporating ecological effects in this
Special Review in the future should the consideration of additional
information indicate that a review would be appropriate.
DATES: Comments, data and information to support or rebut the
presumptions in this Notice and other relevant information must be
received on or before March 23, 1995.
ADDRESSES: Submit three copies of written comments bearing the document
number [``OPP-30000-60''], by mail to: Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring comments to Rm. 1132, CM #2,
1921 Jefferson Davis Highway, Arlington, VA. Telephone: 703-305-5805.
Comments and data may also be submitted electronically by any of
three different mechanisms: by sending electronic mail (e-mail) to:
[email protected]; by sending a ``Subscribe'' message to
[email protected] and once subscribed, send your
comments to OPP-30000-60; or through the EPA Electronic Bulletin Board
by dialing 202-488-3671, enter selection ``DMAIL,'' user name ``BB--
USER'' or 919-541-4642, enter selection ``MAIL,'' user name ``BB--
USER.'' Comments and data will also be accepted on disks in WordPerfect
in 5.1 file format or ASCII file format. All comments and data in
electronic form should be identified by the docket number OPP-30000-60.
Electronic comments on this Notice, but not the complete record,may be
viewed or new comments filed online at many Federal Depository
Libraries. Additional information on electronic submissions can be
found in Unit XIII. of this notice.
Information submitted in any comment concerning this Notice may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). Information so marked will
not be disclosed except in accordance with procedures set forth in 40
CFR part 2. A copy of the comment that does not contain CBI must be
submitted for inclusion in the public docket. Information not claimed
as confidential or not clearly labeled as containing CBI will be placed
in the public file and will be disclosed publicly by EPA without
further notice to the submitter. All non-CBI written comments will be
available for inspection in Room 1132 at the Virginia address given
above from 8 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. No CBI should be submitted through e-mail.
FOR FURTHER INFORMATION CONTACT: By mail: Joseph E. Bailey, Review
Manager, Special Review and Reregistration Division (7508W), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. Office location and telephone number: Special
Review Branch, 3rd Floor, Crystal Station, 2800 Jefferson Davis
Highway, Arlington, VA. Telephone: 703-308-8173. For a copy of
documents in the public docket, to request information concerning the
Special Review, or to request indices to the Special Review public
docket, contact the Public Response and Program Resources Branch, Field
Operations Division (7506C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Telephone: 703-305-5805.
SUPPLEMENTARY INFORMATION: This Notice describes the Special Review
process and the basis for the Agency's decision to initiate this
Special Review. The Notice also requests public comment on the
triazines including information on their toxicity, possible human and
environmental exposure and risks, the benefits of current use, and the
risks and benefits of potential chemical and non-chemical alternatives
to the triazines. Regarding the benefits of the triazines and their
alternatives, the Agency is especially interested in information on use
patterns and farming practices that are likely to result in reduced
pesticide use and to promote solutions to weed control compatible with
the Agency's Sustainable Agriculture and Integrated Pest Management
goals. Procedures for submission of public comments to the Agency are
described in Unit XIII of this Notice.
This Notice is organized into 15 Units. Unit I describes the
Special Review process, legal requirements for the registration of
pesticides, and a summary of the Agency's rationale for initiating this
Special Review of atrazine, simazine and cyanazine. Unit II summarizes
the registration and reregistration history of the triazines as well as
interim risk reduction measures that have been implemented. Unit III
describes the results of animal studies submitted to the Agency to
support continued registration of the triazine herbicides including
discussions regarding the toxic effects of the triazines. Agency
comments relative to registrants' responses to the preliminary
notification to initiate this Special Review for human carcinogenic
effects are also discussed in Unit III. Dietary exposure to the
triazine herbicides through food is presented in Unit IV. This unit
discusses the measurement of dietary residues of concern and estimation
of exposure. Unit V presents the Agency's dietary risk assessment. Unit
VI discusses the exposure to triazine herbicides through contaminated
drinking water and compares safe drinking water standards to ground and
surface water monitoring and detections. The environmental fate of the
triazines is also discussed in this unit. Unit VII discusses the risk
estimates from exposure to triazine-contaminated drinking water and the
registrants' responses to the preliminary notification to initiate
Special Review for such risks. Unit VIII discusses triazine exposure
and risk estimates from non-dietary sources. Unit IX provides
estimations of additive cancer risks from several exposure pathways and
chemicals. Ecological exposure and effects of the triazine herbicides
are presented in Unit X. This unit discusses ecosystem effects, the
effects of triazines on non-target plants and animals and the Agency's
comments relative to the registrants' responses to the preliminary
notification to initiate Special Review for these concerns. Unit XI
presents a use profile of the triazine herbicides and requests
information on sustainable agriculture/IPM and reduced pesticide use.
Unit XII discusses the requirement for registrants to submit
information about unreasonable adverse effects associated with
pesticide use and Unit XIII invites interested parties to comment on
this Notice. Unit XIV summarizes materials available in the public
docket for the triazines and Unit XV lists the references used in
preparing this Notice.
I. Background
A. Special Review Process
The Special Review process provides a mechanism to permit public
participation in EPA's deliberations prior to issuance of any Notice of
Final Determination describing the regulatory action which the
Administrator has selected. The Special Review process is described in
40 CFR part 154, published in the Federal Register of November 27, 1985
(50 FR 49015). During the Special Review process the Agency: (1)
announces and describes the basis for the Agency's finding that use of
the pesticide meets one or more of the risk criteria set forth in 40
CFR 154.7; (2) establishes a public docket; (3) solicits comments from
the public regarding whether the use of a pesticide product as
currently registered or as it is proposed to be registered satisfies
any of the risk criteria for initiation of Special Review set forth at
40 CFR 154.7, or whether any risks posed by the use or proposed use of
the product that satisfy risk criteria at 40 CFR 154.7 are
unreasonable, taking into account the economic, social, and
environmental costs and benefits of the use of the product; and what
regulatory action, if any, the Agency should take with respect to the
use of the product; (4) solicits comment from the Secretary of
Agriculture and the Scientific Advisory Panel if the Administrator
proposes to cancel, deny, or change the classification of the
registration of a pesticide product which is the subject of Special
Review, or to hold a hearing under FIFRA section 6(b)(2) on whether to
take any of those actions; (5) reviews and responds to all significant
comments submitted in a timely manner; and (6) makes a final regulatory
decision based on the balancing of risks and benefits associated with
the pesticide's use.
Issuance of this Notice means that potential adverse effects that
may be associated with the use of pesticide products containing
atrazine, simazine or cyanazine have been identified and will be
examined further to determine their extent and whether, when considered
together with the benefits of these pesticides, such risks are
unreasonable.
B. Legal Requirements
A pesticide product may be sold in the United States only if it is
registered or exempt from registration under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) as amended (7 U.S.C. 136 et
seq.). Before a product can be registered it must be shown that it can
be used without ``unreasonable risk to man or the environment, taking
into account the economic, social, and environmental costs and benefits
of the use of the pesticide'' [FIFRA section 2(bb)]. The burden of
proving that a pesticide meets this standard for registration is, at
all times, on the proponent of initial or continued registration. If at
any time the Agency determines that a pesticide no longer meets this
standard, the Administrator may cancel this registration under section
6 of FIFRA.
C. Preliminary Notification
Prior to the public announcement of initiation of a Special Review,
pursuant to 40 CFR 154.21, registrants of the affected pesticide are
given preliminary notification that the Agency is considering
initiating a Special Review. Registrants are given 30 days to respond
in writing to dispute the validity of the Agency's conclusions or to
present any information in response to the Agency's risk concerns
included in this notification.
EPA issued preliminary notifications of its intention to initiate a
Special Review of atrazine, simazine and cyanazine to all registrants
of these chemicals on February 8, 1994 (Refs. 1, 2, and 3). This
notification included a brief statement of the Agency's concerns. The
data and preliminary risk assessments triggering this Special Review
are described in detail in subsequent units of this notice. A
discussion of registrants' responses to the preliminary notifications
is also included.
D. Determination to Initiate Special Review
The Agency has determined that the estimated risks to humans posed
by atrazine, simazine and cyanazine warrant the initiation of a Special
Review of each of these chemicals. The Agency has also determined that
a combined Special Review of atrazine, simazine and cyanazine is more
appropriate than examining each individually. This determination is
based on the following considerations: all three (1) are structurally
related chemicals, (2) induce mammary tumors when fed to rats and are
classified as Group C, possible human carcinogens, (3) degrade or
metabolize to similar degradates/metabolites, (4) are generally similar
in terms of environmental fate including relative persistence,
leachability, run-off potential and possibly atmospheric transport, (5)
are similar in toxicity to aquatic organisms and terrestrial plants,
and (6) may serve as alternatives to each other for some situations.
The Agency is concerned about the potential excess individual
lifetime cancer risks resulting from dietary exposure to triazine-
treated food/feed commodities as well as the potential cancer risks to
persons mixing, loading and applying products containing the triazine
herbicides, including residential exposure to persons using lawn care
products containing atrazine. EPA is also concerned about the potential
risks resulting from the consumption of drinking water (from ground and
surface water sources) contaminated with triazines and their degradates
(metabolites), in particular the chloro degradates. Furthermore, the
Agency is concerned about the additive impacts that may occur to
persons exposed to more than one triazine, or through more than one
exposure pathway.
While the Agency is also concerned about the potential harmful
impacts on nontarget organisms (aquatic organisms, terrestrial plants)
and their ecosystems that may result from continued use of triazine
herbicides, it is not, at this time, including ecological effects in
this Special Review. The Agency's concerns regarding ecological effects
of the triazines are discussed more fully in Unit X of this notice.
II. Regulatory History of the Triazine Herbicides
This unit summarizes the registration and reregistration history of
the triazines including the Data Call-In Notices (DCIs) issued for
atrazine, simazine and cyanazine and interim risk reduction measures
imposed during the course of the Agency's review of the triazines.
A. Atrazine
Ciba Plant Protection (formerly Ciba-Geigy Corporation) first
registered atrazine in 1959 and remains the lead registrant of the
technical compound from which most end-use products are formulated.
Ciba is responsible for generating data to support the continued
registration of products containing this chemical. Other atrazine
technical registrants are Oxon Italia S.P.A. and Drexel Chemical
Company. Altogether, there are currently 36 registrants with a total of
98 registrations for products containing atrazine.
In 1983, EPA issued a Registration Standard for atrazine. The
Standard noted the Agency's concern about the dietary carcinogenic risk
from ground and surface water contamination. In 1988, EPA issued a
preliminary notification of the Agency's intention to initiate Special
Review to atrazine registrants based on concerns regarding the
carcinogenic potential of atrazine and possible risks resulting from
exposure to atrazine in the diet from treated food and from
contaminated drinking water. Another concern surrounded the potential
carcinogenic risks to workers exposed while mixing, loading and
applying products containing this chemical (Ref. 4). A Data Call-In
Notice (DCI) issued in November 1988 required submission of information
regarding results of ground and surface water monitoring and use and
usage data.
In 1989, EPA notified registrants of an additional concern based on
the results of a laboratory study showing atrazine cardiotoxicity
(heart damage) in dogs (Ref. 5). The Agency issued a DCI requiring an
additional study in order to further explore the findings regarding
cardiac effects. Since that time, the Agency's concerns regarding
cardiotoxicity have been resolved and are discussed in Unit VIII of
this Notice.
In 1990, the Agency accepted proposed voluntary risk reduction
measures from Ciba which included label amendments that reduced
application rates of atrazine and classified the chemical as a
``Restricted Use Pesticide'' based on ground water concerns for
agricultural uses. (Commercial, home and garden, and turf/lawn care
uses were not restricted.) These risk reduction measures partially
addressed EPA's ground water concerns largely by implementing measures
to reduce the potential for point-source contamination.
In September 1990 as part of the reregistration requirements for
atrazine, the Agency issued a comprehensive DCI listing all remaining
atrazine data requirements. In April 1992, EPA accepted additional
voluntary proposals by atrazine registrants to further restrict
atrazine use including protective measures to partially address the
Agency's concerns regarding atrazine contamination of surface water.
These restrictions included reducing maximum application rates,
deleting some uses and establishing set-backs and buffer zones from
surface water for mixing, loading and application. The registrant also
undertook research studies to help determine the effects of set-backs
on water quality and to further determine atrazine contamination of
lakes and reservoirs.
B. Simazine
Ciba first registered simazine in 1957 and currently produces
approximately 80 to 90 percent of the technical product. There are two
other technical registrants: Oxon Italia and Drexel. There are a total
of 16 registrants with 38 registered products containing simazine.
The Registration Standard for simazine, issued in March 1984,
expressed the Agency's concern about simazine's potential for ground
water contamination and classified it as a ``Restricted Use Pesticide''
based on this concern. In 1985, the Agency withdrew simazine's
``Restricted Use'' classification and imposed both ground water
advisory and aquatic invertebrate toxicity statements on the label.
In August 1989, EPA issued a DCI requiring ground and surface water
monitoring information and simazine use data. EPA issued a
comprehensive DCI in September 1991 requiring data for reregistration
including toxicological and residue data. In response to the DCI, Ciba
elected not to support the aquatic uses of simazine and subsequently
voluntarily cancelled these uses on all of its registered products
(Ref. 6).
In August 1993, EPA conducted a risk assessment for simazine
algaecide products used in swimming pools, hot tubs and whirlpools, and
concluded that water treated with simazine algaecides posed
unacceptable cancer and non-cancer health risks to children and adults.
After completing the risk assessment, the Agency notified the
registrants of its concerns. Most registrants requested voluntarily the
cancellation of their end-use products registered for such uses with no
provisions for use of existing stocks. The cancellation order for these
products was effective April 15, 1994 (Ref. 7). The remaining products
for which voluntary cancellation was not requested were cancelled
through a Notice of Intent to Cancel published in the Federal Register
on July 7, 1994 (Ref. 8). When the final cancellation order became
effective, further sale, distribution and use of existing stocks of
products for these uses was prohibited.
C. Cyanazine
In 1971, Shell Chemical Company first registered cyanazine under
the trade name Bladex. DuPont Agricultural Products and Ciba Plant
Protection are now the only registrants. DuPont, having the only
technical registration, takes the lead in generating data to support
continuing registration.
The cyanazine Registration Standard, issued by EPA in December
1984, classified this chemical as a ``Restricted Use Pesticide'' based
on its detection in ground and surface water. Label statements
regarding developmental toxicity concerns and ground and surface water
detections were added to cyanazine labels but did not explicitly link
the restricted use classification to these concerns. A Special Review
of cyanazine was initiated in April 1985 based on studies showing
developmental toxicity in two species after oral administration of the
chemical. Estimated risks to mixer/loaders and applicators were of
concern. Dermal developmental toxicity studies were submitted that led
to a refinement of the risk assessment and a determination that if
additional risk reduction measures were adopted, occupational risks
would be partially mitigated. The Special Review was concluded in 1988
by requiring the use of protective gloves, chemical-resistant aprons
for mixer/loaders and closed mixing/loading systems for aerial
application and chemigation (application of pesticides through
irrigation). The Agency also required revised label language
specifically linking cyanazine's ``Restricted Use'' status to its
developmental effects. Because of the detections of cyanazine in ground
water, the Agency determined that the ground water advisory statement
was appropriate for cyanazine labels.
In January 1991, EPA issued a DCI requiring information on the
results of cyanazine ground water monitoring data to upgrade a
monitoring study for cyanazine and one metabolite.
In April 1992, as part of the reregistration of cyanazine, EPA
issued a DCI requiring residue chemistry, environmental fate and
ecological effects data. For Special Review purposes, the DCI also
required the registrants to submit all existing data on usage, pest
management, comparative product performance and pest resistance data.
These data were received in October 1992.
In 1993, the Agency approved label use restrictions proposed by the
cyanazine registrants to partially address the Agency's ground and
surface water concerns. Label amendments include reduced maximum
application rates and surface water set-backs, similar to those
previously approved for atrazine in 1992.
III. Toxicity of Atrazine, Simazine and Cyanazine
In laboratory animal studies, all three triazines induce mammary
tumors in one strain of one species (the female Sprague-Dawley rat)
and, based on a weight-of-evidence approach, all three chemicals are
classified by EPA as Group C (possible human) quantified carcinogens.
This unit describes the results of required and voluntary toxicological
laboratory data and other studies submitted in support of the continued
registration of the triazine herbicides, the Agency's cancer
classification of the triazines, findings by the EPA Cancer Peer
Reviews and the FIFRA Scientific Advisory Panel (SAP), and the
registrants' position regarding the Agency's cancer risk assessment.
A. Atrazine
1. Carcinogenicity-- a. Rat study. Atrazine was administered in the
daily diet of Sprague-Dawley rats (50/sex/dose) at doses of 0, 10, 70,
500, or 1,000 ppm for 2 years. An additional 10 rats per sex were
placed on control (0 ppm) and high dose (1,000 ppm) diets for 12- and
13-month sacrifices (Ref. 9). Administration of atrazine to female rats
was associated with a statistically significant increase in mammary
gland fibroadenomas at 1,000 ppm; mammary gland adenocarcinomas
[including two carcinosarcomas at the highest dose tested (HDT)] at 70,
500, and 1,000 ppm; and total mammary gland tumor-bearing animals at
1,000 ppm in comparison to control animals. In males, the incidence of
testicular interstitial cell tumors was increased at the high dose in
comparison to controls. This increase was associated with a significant
dose-related trend driven by high dose effect; however, this
statistically significant increase was within the historical control
range. There was an increase in retinal degeneration and in
centrilobular necrosis of the liver in high-dose females and an
increase in degeneration of the rectus femoris muscle in high-dose
males and females when compared to controls. Based on decreased body
weight gain, the Lowest-Observed-Effect Level (LOEL) for chronic
toxicity in males and females is 500 ppm and the No-Observed-Effect
Level (NOEL) is 70 ppm.
b. Mouse study. Atrazine was administered in the daily diet of CD-1
(Charles River Laboratories) mice (60/sex/dose) at 0, 10, 300, 1,500 or
3,000 ppm for 91 weeks (Ref. 10). Administration of atrazine to mice
was not associated with any treatment-related changes in the incidence
of palpable masses in male or female mice. No statistically significant
increases in incidence were found for the following types of neoplasms:
mammary adenocarcinomas, adrenal adenomas, pulmonary adenomas and
malignant lymphomas. The LOEL and NOEL are determined to be 1,500 ppm
and 300 ppm, respectively, based upon decreases in mean body weight
gain at 91 weeks.
c. Mutagenicity. Mutagenicity studies evaluate the potential for a
chemical to promote genetic alterations in cells. The registrant has
submitted five mutagenicity studies that meet EPA guideline
requirements using atrazine. The results of these studies are negative.
The registrant also performed an unscheduled DNA synthesis (UDS) assay
to satisfy remaining reregistration requirements. The Agency's review
of this study concluded that atrazine did not induce UDS in primary rat
hepatocytes.
d. Cancer classification. There have been three Office of Pesticide
Programs (OPP) Carcinogenicity Peer Reviews to evaluate atrazine's
carcinogenic potential. Two reviews were conducted prior to submission
of this chemical to the SAP for review, and one subsequent to the SAP
review.
The first Carcinogenicity Peer Review Committee met in September
1987 and concluded that the available data provided limited evidence
for the carcinogenicity of atrazine in rats. The Committee tentatively
classified atrazine as a Group C (possible human) carcinogen based on
an increased incidence of mammary tumors in female Sprague-Dawley rats.
While awaiting an acceptable mouse carcinogenicity study, the Committee
concluded that a quantitative risk assessment should be performed due
to the induction of mammary gland tumors and possible decreased latency
for their appearance, and the structural similarity to other then-
registered triazine herbicides classified as Group C carcinogens (Ref.
11).
A second Carcinogenicity Peer Review was held in June 1988 and
confirmed the earlier findings. This review included an evaluation of
the mouse carcinogenicity study, in which no compound-related
carcinogenic effects were observed (Ref. 12).
In September 1988, the OPP Carcinogenicity Peer Review Committee
presented its position to the SAP. The SAP agreed with the Group C
classification but not with a Q1* approach to quantify risks (Ref.
13). The SAP stated that the variability of the endpoint and its
potential for secondary hormonal influence, as suggested by endocrine
imbalance at high, but not low, doses indicated that the proposed
quantitative risk assessment was inappropriate for this chemical.
Shortly after the SAP presentation, a third Peer Review of atrazine
was held and, upon reevaluation of the available data and the SAP
comments, the OPP Carcinogenicity Peer Review Committee determined that
the data were not appropriate for quantitative risk assessment and that
the registrant should continue to generate data to support a hormonal
mechanism of carcinogenicity (Ref. 13). In November 1988, the Committee
reevaluated their decision from the third Peer Review and reverted to
their original conclusion that a quantitative risk assessment for
atrazine was appropriate (Ref. 14). The Committee based its decision to
quantify the risk on a weight-of-evidence approach including the
following considerations: (a) tumors in one species (rat) and one sex
(female); (b) an increase in primarily malignant type tumors
(adenocarcinomas) as contrasted with benign types; (c) both
adenocarcinomas and the number of mammary tumor bearing animals were
statistically increased at doses of 70, 500 and 1,000 ppm; (d) a
possible treatment-related increase in rate of tumor appearance; and
(e) the structure activity relationship between atrazine and other
compounds of known carcinogenic potential. The Committee concluded that
there were still insufficient data to support a hormonal mechanism
theory.
e. Determination of the Q1*. The Agency uses the linearized
multi-stage model to extrapolate from effects seen at high doses in
laboratory studies to predict tumor response at low doses. This model
is based on the biological theory that a single exposure to a
carcinogen can initiate an irreversible series of transformations in a
single cell that will eventually lead to tumor formation. In addition,
the linearized multi-stage model assumes that the probability of each
transformation is linearly related to the degree of exposure (i.e., a
threshold does not exist for carcinogenicity).
Using this model, the cancer potency estimate in human equivalents
(Q1*) for atrazine is 2.2 x 10-1 (mg/kg/day)-1, which
represents the 95 percent upper confidence limit (UCL) of tumor
induction likely to occur from a unit dose (Ref. 15).
2. Cardiotoxicity. In 1987, atrazine registrants submitted to the
Agency the results of a 1-year chronic dog feeding study in which the
animals were dosed at 0, 0.5, 5 or 34 mg/kg/day. The study authors
concluded that treatment-related effects, EKG alterations and cardiac
lesions, were observed only at the highest dose tested. The Agency's
review of the study resulted in the conclusion that treatment-related
effects were seen at the mid-dose level as well as the high-dose level.
Consequently, the Agency established a NOEL for cardiotoxicity at 0.5
mg/kg/day. The registrant submitted additional individual animal
information on the chronic dog study and after reviewing these data,
the Agency agreed with the registrants that treatment-related effects
were, in fact, seen only at the high-dose level. Accordingly, the NOEL
was increased from 0.5 to 5.0 mg/kg/day based on EKG alterations and
cardiac lesions (Ref. 16).
B. Simazine
1. Carcinogenicity-- a. Rat study. Simazine technical was
administered in the diet to groups of 50 male and female Sprague-Dawley
(S-D) rats at 0 (control), 10, 100 or 1,000 ppm for 2 years. Additional
groups (30-40/sex/dose) were also treated (Ref. 17). The statistically
significant effects in the test animals are as follows:
(1) Female S-D rats. (a) There was a statistically significant
increase in mortality in female rats.
(b) There was a statistically significant dose-related trend for
mammary gland carcinomas and combined adenomas/fibromas/carcinomas;
however, when the shortened life-span of the female rats was included
in the statistical evaluation, the incidences of carcinoma alone at
both the 100 and 1,000 ppm [Highest Dose Tested (HDT)] dosage groups
were statistically significantly increased as well. The upper limit of
the historical control incidence reported for mammary carcinoma was
exceeded at 100 ppm, and greatly exceeded at 1,000 ppm (HDT). The
incidence of cystic glandular hyperplasia in the mammary gland was
statistically significantly increased at the HDT, which correlates with
the observed high tumor incidence at that dose.
(c) There was a statistically significant dose-related trend for
kidney tubule adenomas; however, as in the case of the male rats,
tumors occurred only at the HDT and the incidence was not statistically
significant by pairwise comparison with that in the concurrent control
group. The incidence for adenomas and/or carcinomas reported for
historical controls was zero in all seven available studies.
(d) There were also statistically significant dose-related trends
for adenomas, carcinomas and combined adenoma/carcinomas of the
pituitary gland. The incidence of pituitary gland carcinoma at 1,000
ppm (HDT) only slightly exceeded the upper bound of the historical
control range; it greatly exceeded the incidence reported in six out of
the seven available studies.
(2) Male S-D rats. (a) In male rats, there was a statistically
significant decrease in mortality when compared to females treated with
the same dose.
(b) The incidence of liver tumors was significantly increased for
carcinoma and for combined adenoma/carcinoma at 100 ppm and 1,000 ppm
(HDT), respectively; however, these results fell within the range
reported for historical controls.
(c) There was also a statistically significant dose-related trend
for kidney tubule carcinomas, and for combined adenomas/carcinomas;
however, tumors occurred only at the HDT and neither incidence was
statistically significant by pairwise comparison with that in the
concurrent control.
b. Mouse study. There is no evidence that simazine induces cancer
in the mouse (Ref. 18).
c. Mutagenicity. The Agency has received one acceptable
mutagenicity study, the Salmonella assay, which was negative (Ref. 19).
Published information reports some possibly positive mutagenicity and
genotoxicity studies.
d. Cancer classification. The OPP Carcinogenicity Peer Review for
simazine, held in May 1989, concluded that simazine is a Group C
carcinogen and that carcinogenic risks should be quantified (Ref. 20).
The Committee considered the following to be of importance in its
weight-of-the-evidence determination: similar structure activity
relationship to other s-triazines, particularly atrazine; the same
tumor type as atrazine (mammary gland tumors in the rat); malignant
tumors in the pituitary gland; negative findings for carcinogenicity in
the mouse; and several questionable positive mutagenicity and
genotoxicity studies reported in published literature. The Peer Review
Committee concluded that there were inadequate data to support a
hormonal mechanism theory.
e. Determination of the Q1*. Using the same model described
earlier for estimating the Q1* for atrazine, the cancer potency
equivalent for simazine, based on malignant mammary tumors in the rat,
is estimated at 1.2 x 10-1 (mg/kg/day)-1 (Ref. 21). This
represents the 95 percent UCL of tumor induction likely to occur from a
unit dose.
The SAP review of simazine (September, 1989), while agreeing with
the Group C classification, did not recommend the use of a quantitative
risk assessment. The SAP noted that certain pesticides may alter
endocrine physiology in the rat and influence the incidence of mammary
tumors and recommended that the Agency formulate a position on the
regulation of chemicals with this mechanism. At a subsequent OPP Peer
Review meeting (April, 1990), the Committee evaluated the SAP's
recommendation and concluded that it is appropriate to use a low dose
extrapolation model (Q1*) to quantify the carcinogenic risks of
exposure to simazine unless the registrant provides data showing a
hormonally mediated mechanism of action for the mammary tumor
development (Ref. 22). Data have not been received that support a
hormonal mechanism.
C. Cyanazine
1. Carcinogenicity-- a. Rat study. In a combined chronic toxicity/
carcinogenicity study with cyanazine in Sprague-Dawley rats, groups of
52 males and 52 females were fed cyanazine technical at concentrations
of 0, 1, 5, 25, or 50 ppm in the diet for 2 years (Ref. 23).
Additionally, 10 animals per sex per group were used as a satellite
group for interim sacrifice at 12 months. The highest dose tested was
considered to be adequate for carcinogenicity testing based upon
decreased body weight gain of about 14 percent in both males and
females in the first 3 months of the study. However, the Agency
concluded that the animals could probably have tolerated a higher dose.
Findings from this study include a statistically significant
increase in malignant mammary gland tumors (adenocarcinoma and
carcinosarcoma) in females of the 25 and 50 ppm groups, with a
statistically significant positive trend. The incidences of malignant
tumors were outside the historical control range of 10.1 to 22.7
percent with an average of 17.9 percent.
Generally, there were no non-neoplastic lesions that could be
attributed to treatment with cyanazine, due to a lack of historical
control data. However, three lesions were observed that have not been
reported with other triazine herbicides. These lesions were: (i)
granulocytic hyperplasia of bone marrow in males; (ii) extramedullary
hematopoiesis of the spleen in males; and (iii) demyelination of the
sciatic nerve in females.
b. Mouse study. Findings show that dietary administration of
cyanazine did not alter the spontaneous tumor profile in the CD-1 mouse
(Ref. 24).
c. Mutagenicity. There is some evidence that cyanazine has
mutagenic activity. Of the submitted studies, cyanazine has been found
to be positive in a mouse lymphoma assay (dose-responsive in repeat
assays) and a UDS assay (Ref. 25). Results of another UDS assay in rat
spermatocytes following an in vivo exposure were negative (Ref. 26).
d. Cancer classification. In March 1991, the OPP Carcinogenicity
Peer Review Committee evaluated the weight-of-the-evidence on
cyanazine, with particular emphasis on its carcinogenic potential. The
Peer Review Committee concluded that cyanazine should be classified as
a Group C, possible human carcinogen and recommended quantification of
human risk using a low dose extrapolation model (Q1*) (Ref. 24).
In addition to the mammary gland tumors observed in the female
Sprague- Dawley rat, the weight-of-the-evidence for the carcinogenic
potential of cyanazine includes the evidence that cyanazine is
structurally related to the other chloro-s-triazines which also induce
mammary gland cancer in experimental animals. However, cyanazine
differs structurally from other triazines in that the molecule has a
cyano (nitrile) functional group in the alkyl substituent of one the
amino groups. The presence of this highly reactive cyano group favors a
different metabolic breakdown pathway indirectly indicating that
cyanazine can generate a more electrophilic arylating agent than other
chloro-s-triazines, and is consistent with the finding that cyanazine
has a more positive genotoxicity profile than the other chloro-s-
triazines.
e. Determination of the Q1*. Using the same model described
earlier for estimating the Q1*s for atrazine and simazine, the
cancer potency equivalent for cyanazine, based on development of
adenocarcinomas and carcinosarcomas in female rats, was estimated at
8.4 x 10-1 (mg/kg/day)-1. The Agency's Carcinogen Risk
Assessment Verification Endeavor workgroup has increased the Q1*
to 1.0 x 100 (mg/kg/day)-1 based on a revised oral slope
factor. This represents the 95 percent UCL of tumor induction likely to
occur from a unit dose (Ref. 27). The cancer classification for this
chemical has not been presented to the SAP for review.
D. Epidemiology Data
It is often difficult to establish a link between cause and effect
with human epidemiological data. Such data exist for the triazines but,
as with any data of this type, it is difficult to clearly attribute
findings to triazine exposure. However, the Agency's review of two
Italian field worker studies indicates a possible association between
ovarian cancer and exposure to atrazine and simazine (Ref. 28). In
another study, preliminary results show a correlation between atrazine
concentrations in local areas surrounding Rathbun Lake, Iowa, and birth
defects including heart, urogenital tract and limb reductions (Ref.
29). Also, the Agency has reviewed published summaries of several
cancer epidemiology studies concerning triazine use in the Midwest;
these studies provide some evidence of an association between non-
Hodgkin's lymphoma and triazine exposure, but other explanations or
confounding factors could account for the association (Ref. 30).
Breast cancer in humans and triazine herbicides. Data from
carcinogenicity studies discussed earlier show that there is an
association between the administration of the triazines to Sprague-
Dawley rats and an increase in the incidence of mammary tumors in
female rats. The Agency does not have data or substantial
epidemiological evidence to definitively link the triazine pesticides
to breast cancer in humans; however, reports have been published that
attempt to associate breast cancer in humans to exposure to triazines
(Refs. 31 and 32). The relevance of the mechanism for mammary
tumorigenesis in rats to that in humans has not been documented and
species differences have been found to exist (i.e., cells of origin,
degree of endocrine responsiveness and metastatic potential). The
mechanisms for tumor formation in Sprague-Dawley rats and the
implications for causing breast cancer in humans are currently being
investigated. Until there are data to definitively refute or support
the possibility for certain triazines to be human mammary carcinogens,
the Agency must regulate these compounds based on the available animal
data and the assumption that the chemicals' potential to cause cancer
in animals may indicate the possibility that they can cause cancer in
humans.
E. Registrants' Response to Preliminary Notification Concerning
Carcinogenic Risks and Agency Comments
Responses to the Agency's preliminary notification were received
from Ciba for atrazine and simazine, and from DuPont for cyanazine.
Both registrants responded with regard to the Agency's concern
regarding cancer risks associated with exposure to the triazine
herbicides. Ciba and DuPont contend that the exact mechanism of the
strain-specific mammary gland tumorigenesis in Sprague-Dawley rats has
not yet been elucidated, and therefore, the association of cancer risks
in animals to human cancer risks should not be drawn. Ciba indicated a
willingness in its response to conduct additional research on the
strain-specific response to atrazine and requested that the Agency
consider additional research before reaching conclusions about the
cancer causing potentials of atrazine and simazine. DuPont indicated in
its response that research is currently being conducted to determine
the mechanism of cyanazine-induced mammary gland tumors; this research
is expected to be completed in late 1995. Both registrants requested
that the Agency consider this additional information before reaching
definitive conclusions about triazine cancer risks.
In response to the above comments received from Ciba and DuPont,
the Agency's position is that, as of the publication of this notice,
all information available concerning the carcinogenic potential of
atrazine, simazine and cyanazine has been considered in the Agency's
occupational and dietary risk assessments. The Agency believes that the
current method of quantifying cancer risks using the Q1* is
appropriate considering the available data. To date, Dupont has
submitted no reports or studies that show the mechanism by which
cyanazine induces tumors. Ciba submitted a four-part voluntary hormonal
study for atrazine to address the issue of a hormonal threshold
mechanism. Because of the similarities between atrazine and simazine,
the registrant contends that conclusions drawn regarding atrazine will
also apply to simazine. The Agency has considered the information
provided by Ciba that attempts to explain the mechanism of mammary
tumorigenesis in rats exposed to atrazine but concludes that the data
do not actually explain any such mechanism and therefore are not
adequate to support a mechanism of action operating through a hormonal
mechanism and/or threshold (Refs. 33, 34, and 35). If the registrants'
theory that the mammary tumors seen in laboratory studies of the
triazines is, at some future date, proven to be the result of a
hormonal imbalance in the rat that occurs only at higher doses, the
Agency could choose to quantify the risk using an MOE/RfD or other
approach rather than using a Q1*. However, based on available
data, the Q1* serves as the regulatory endpoint.
Ciba has also hypothesized that the differences in mammary tumor
response to atrazine by Sprague-Dawley and Fischer 344 rats can be
attributed to differences in endocrinology between the strains. To
address the issue of the effects being strain-specific, Ciba submitted
a voluntary study comparing the effects of atrazine on Sprague-Dawley
and Fischer rats. However, the Agency does not believe that the data
provided by Ciba adequately support the theory that reproductive
hormonal differences between the two strains accounts for the
differences in tumor response (Ref. 33).
An International Life Sciences Institute/Risk Science Institute
(ILSI) workgroup is examining the suitability of the Sprague-Dawley rat
as a model for mammary tumor formation in humans. If the Agency were to
agree with a conclusion that the Sprague-Dawley is not an appropriate
model, the weight-of-evidence determination for the triazines would in
all likelihood be modified. That is, they may no longer be classified
as possible human carcinogens. The ILSI workgroup is expected to issue
a background report discussing the state of the science on this issue
by the end of 1994.
Ciba has stated that atrazine-induced endocrinologic changes in the
female Sprague-Dawley rat are not relevant to mammary tumorigenesis in
human females. The Agency acknowledges that not all of the risk factors
associated with the etiology of human breast cancer are known; however,
the Agency believes that some parallels may exist in terms of the cause
of initiation and development of mammary tumors in female rodents and
humans. Finally, the Agency does not want to preclude the possibility
that the potential for tumorigenesis at other target sites may exist in
humans as a result of exposure to the triazines. The Agency will
consider and appropriately incorporate into its risk assessments any
additional data provided that may better characterize the
carcinogenicity of the triazine herbicides during the course of this
Special Review.
IV. Triazine Dietary (Food/Feed) Exposure
Human dietary exposure to the triazines can occur from residues
remaining in or on treated crops including corn, orchard fruits, nuts
and sugarcane. Dietary exposure to the triazines may also occur from
consumption of residues in animal commodities including meat, milk,
poultry and eggs, that result from animals having been fed triazine-
treated crops (including corn, sorghum and sugarcane). This unit
describes the Agency's assessment of human dietary exposure to the
triazines and the uncertainties associated with that assessment.
Triazine dietary risks are summarized in Unit V of this notice. In
triazine use areas, human exposure may also occur through contaminated
drinking water from ground or surface water sources. A discussion of
exposure and risks from triazine-contaminated drinking water is
presented in Units VI and VII of this notice.
A. Toxic Residues of Concern
In estimating triazine dietary risks, the Agency assumes that the
total toxic residue of concern is the parent triazine compound plus all
metabolites with a triazine ring, including among others, all chloro
and hydroxy metabolites. When there are insufficient data concerning
the toxicity of metabolites, it is the Agency's policy to make the
conservative assumption that structurally-related metabolites are as
toxic as the parent compound. Therefore, in estimating risks, it is
appropriate to consider all of the triazine metabolites measured as
well as the parent compounds.
In plants, atrazine and simazine are metabolized to numerous
metabolites, no one of which has yet been shown to comprise a large
portion of the total terminal residue. Metabolic processes include N-
dealkylation and conjugation with endogenous plant components,
particularly glutathione, and hydroxylation. Most metabolites have been
shown to contain the intact triazine ring. In soils, atrazine and
simazine are metabolized to dealkylated chloro metabolites and hydroxy
analogues of the parent compounds. The dealkylated chloro metabolites
tend to be more mobile in soils than the hydroxy parent analogues.
In animals, data have been provided showing the animal metabolism
of atrazine, simazine, and corn metabolites of atrazine (animals were
fed corn which had been treated with atrazine). Higher tissue residues
resulted from feeding atrazine or simazine, and numerous metabolites
were identified resulting from N-dealkylation and conjugation with
glutathione followed by modification of the glutathione moiety. In most
cases, no single metabolite accounted for a significant percentage of
the total residue. Exceptions to this were milk in which the di-N-
dealkylated chloro metabolite (G-28273) comprised approximately 30
percent of the total residue for atrazine, and liver in which the
cysteine conjugate of G-30033 comprised approximately 25 percent of the
total residue. When corn treated with atrazine was fed to animals, much
lower residues resulted in tissues indicating less absorption of
metabolites than of the parent compounds.
The metabolism of cyanazine in plants is slightly different from
that of atrazine and simazine in that a limited number of metabolites
(Ref. 9) comprise most of the terminal residue. Cyanazine metabolites
result from a combination of ring hydroxylation (displacement of
chlorine), deethylation, and oxidation of the cyano group to form
amides and acids.
Although the metabolism of cyanazine in animals is not yet
adequately understood, preliminary information suggests that some of
the same metabolites found in plants are also found in animals.
B. Anticipated Residues
The Agency presently considers the triazine chloro metabolites to
possess equivalent potency to the parent compounds with regard to
carcinogenicity; however, this assumption is made from studies in which
animals were fed parent compound only. Based on its assessment of the
structure-activity relationship and potential carcinogenicity of all
registered triazine compounds, EPA believes metabolites which have been
dechlorinated may be less potent carcinogens than the parent compounds.
An interim report on a voluntary hydroxyatrazine carcinogenicity study,
which indicated negative findings at the end of 1 year, supports this
hypothesis. A second interim report has been received and is currently
being reviewed by the Agency. However, in the absence of completed
laboratory studies on the carcinogenicity of the hydroxy metabolites,
the Agency has relied on its equivalency policy and has made the
assumption that all metabolites containing the triazine ring are
equipotent as carcinogens as the parent compound when conducting its
risk assessment. If the data in the final report are available in a
timely fashion and indicate that the hydroxy metabolites are not
carcinogenic, the Agency will then base its dietary exposure and cancer
risk assessment for atrazine and simazine on the parent compounds plus
those metabolites other than the hydroxy metabolites. As a result, the
estimated dietary cancer risks for atrazine and simazine would appear
to be reduced compared with current estimates. A decision has not yet
been made by the Agency on how the results of the hydroxyatrazine
carcinogenicity study will affect which metabolites are included in the
risk assessment for cyanazine. The final results of the hydroxyatrazine
study are expected in early 1995.
1. Atrazine and simazine. For atrazine and simazine, the Agency has
based its current dietary risk assessment on both radiolabel studies
(both field and greenhouse) and field trials (non-radiolabel studies).
Estimated residue levels were determined using radiolabel studies for
corn, sorghum and animal commodities. Field trial data were used for
all other commodities. Residue estimates from radiolabel studies
include residues of all triazine ring containing metabolites. Residue
estimates from field trials include either the parent compound only, or
the parent compound plus chloro metabolites. The best available data
currently indicate that the parent and chloro metabolites comprise only
a small portion (less than 5 percent) of the total triazine ring
residue in most commodities.
These data introduce uncertainty into the dietary risk assessment
for two major reasons. First, when field trial data are used, only a
small portion of the total toxic residue is considered in the risk
assessment. Because the percentage of parent plus chloro metabolites
relative to the total triazine ring residue would be expected to vary
somewhat from crop to crop, the percentage of the total estimated risk
accounted for by these data is not known, but will always lead to an
underestimate of risk when detectable residues are present. Second, no
detectable residues were found in many commodities, particularly for
simazine. Where there are no detectable residues, the Agency assumes
that the residues are 1/2 the analytical method limit of detection
(LOD). The actual residues could be far less than 1/2 the LOD leading
to an overestimation of the risk or greater than 1/2 the LOD but less
than the LOD leading to an underestimate.
Since the registrants have been unable to develop analytical
methodology which measures total triazine ring residues in non-
radiolabel field trials, radiolabel field studies currently provide the
best data to use for risk assessment. New radiolabel field studies for
major dietary risk contributors for both atrazine and simazine have
been submitted to the Agency and are currently under review.
Preliminary reviews of the data do not indicate that currently
estimated dietary risks will change significantly.
2. Cyanazine. The sources of information for calculating all
anticipated residues of cyanazine in crop commodities were residue data
from field trials and processing studies and, in some cases, data
translated from metabolism studies (Ref. 36).
Cyanazine metabolism studies indicate that regulated metabolites
account for greater than 90 percent of the total triazine ring-
containing residue. Because a small set of discrete, measurable
metabolites make up a large portion of the total triazine ring residue,
field radiolabel studies are not necessary for cyanazine. Therefore,
the Agency's dietary risk assessment is not expected to change based on
submission of additional residue data.
V. Triazine Dietary (Feed/Food) Risk Assessment
A. Dietary Cancer Risks
Dietary (food/feed) cancer risks for the triazines were estimated
for the overall U.S. population using the following relationship:
Upper bound estimated carcinogenic risk = Dietary exposure
(Anticipated Residue Contribution) x Q1*.
It should be remembered that the Agency's procedures for
quantifying cancer risks actually identifies a range, rather than just
a single value. The upper boundary on that range is the risk using the
upper 95 percent confidence limit on the toxicology data. The lower
boundary on the range is zero. Thus, actual risk to humans may be as
low as zero. Toxicological studies and calculation of Q1*s for
atrazine, simazine and cyanazine were described in Unit III of this
notice; dietary exposure assumptions were described in Unit IV of this
notice.
1. Atrazine cancer risk estimates. The dietary risk assessment for
atrazine was conducted based on total triazine ring residues for corn,
sorghum and animal commodities, and on parent, or parent and chloro
metabolite residues for all remaining crops. This analysis resulted in
a combined estimated upper bound carcinogenic risk of 4.4 x 10-5
for all commodities with sugarcane being the largest single contributor
to total atrazine risk (Ref. 37). Excluding sugarcane, the total
atrazine carcinogenic risk is estimated to be 2.2 x 10-5. Other
major risk contributors are milk, sweet corn, corn (other), red meat
and eggs. The dietary cancer risk estimates for atrazine are provided
in Table 1:
Table 1.--Dietary Cancer Risk Estimates for Atrazine
(FT = field trial data (parent, or parent + chloro). R = radiolabel data
(total triazine ring)).
------------------------------------------------------------------------
Type Anticipated Percent Exposure Upper Bound
Commodity Data Residue Crop (mg/kg/ Cancer Risk
Used (ppm) Treated day) Estimates
------------------------------------------------------------------------
Corn, sweet..... R 0.10 60 1.4 x 3.1 x 10-6
Corn, other..... R 0.10 70 2.4 x 5.3 x 10-6
10-5
Eggs........... R 0.01 (eggs, - 5.8 x 1.3 x 10-6
yolks) 10-6
0.009
(whites)
Guava........... FT 0.01 10 -\1\ 0
Macadamia nuts.. FT 0.10 70 3.0 x 6.6 x 10-10
10-9
Milk........... R 0.004 - 4.2 x 9.2 x 10-6
10-5
Millet.......... FT 0.68 1 -\1\ 0
Pineapple....... FT 0.03 20 4.0 x 9.0 x 10-8
10-7
Poultry meat.... R 0.0006 - 3.1 x 6.8 x 10-8
(meat, 10-7
fat) 0.002
(liver)
Redmeat........ R 0.004 - - 9.3 x 2.1 x 10-6
0.02\2\ 10-6
Sorghum........ R 0.13 70 2.2 x 4.8 x 10-7
10-6
Sugarcane....... FT 0.16 80 1.0 x 2.2 x 10-5
10-4
Wheat.......... FT 0.02 1 2.8 x 6.2 x 10-8
10-7
------------------------------------------------------------------------
Total......... 4.4 x 10-5
Total 2.2 x 10-5
(excluding
sugarcane).
------------------------------------------------------------------------
\1\ Exposure values for these commodities are extremely low.
\2\ Range of values were used for meat, liver and kidney.
2. Simazine cancer risk estimates. Dietary cancer risk estimates
for simazine are based on translated atrazine data for corn and animal
commodities. The total estimated dietary risk from all commodities is
1.4 x 10-5 (from all registered commodities, the risk is 1.1 x
10-5) (Ref. 38). (Note that estimates are based on half the limit
of detection for most commodities.) The risk from simazine use on
oranges is a major contributor to total risk, as is the risk from
apples. Corn contributes only a small percent of the total simazine
risk because of the low percent crop treated. The dietary cancer risk
estimates for simazine are provided in Table 2:
Table 2.--Dietary Cancer Risk Estimates for Simazine
(FT = field trial data (parent, or parent + chloro). R = radiolabel data
(total triazine ring)).
------------------------------------------------------------------------
Type Anticipated Percent Exposure Upper Bound
Commodity Data Residue Crop (mg/kg/ Cancer Risk
Used (ppm) Treated day) Estimates
------------------------------------------------------------------------
Almonds......... FT 0.10 45 1.3 x 1.6 x 10-8
Apples......... FT 0.05 40 1.6 x 1.9 x 10-6
10-5
Avocados....... FT 0.05 30 1.9 x 2.3 x 10-8
10-7
Bananas/Plantai FT 0.02 10 4.7 x 5.6 x 10-8
ns. 10-7
Blueberries..... FT 0.05 100 4.5 x 5.4 x 10-8
10-7
Caneberries..... FT 0.05 100 7.2 x 8.6 x 10-8
10-7
Cherries........ FT 0.10 45 1.7 x 2.0 x 10-7
10-6
Corn,sweet..... R 0.10 5 1.2 x 1.4 x 10-7
10-6
Corn,other..... R 0.10 2 6.8 x 8.2 x 10-8
10-7
Cranberries..... FT 0.05 100 1.7 x 2.0 x 10-7
10-6
Currants....... FT 0.05 100 2.7 x 3.2 x 10-9
10-8
Eggs........... R 0.0003 - 1.8 x 2.2 x 10-8
10-7
Filberts....... FT 0.10 100 4.0 x 4.8 x 10-9
10-8
Grapefruit..... FT 0.05 45 5.2 x 6.2 x 10-7
10-6
Grapes......... FT 0.05 35 3.9 x 4.7 x 10-7
10-6
Lemons.......... FT 0.05 50 1.0 x 1.2 x 10-7
10-6
Macadamia nuts.. FT 0.10 100 5.0 x 6.0 x 10-10
10-9
Milk........... R 0.00007 - 7.4 x 8.9 x 10-8
10-7
Olives......... FT 0.05 18 1.0 x 1.2 x 10-8
10-7
Oranges......... FT 0.05 45 4.8 x 5.8 x 10-6
10-5
Peaches......... FT 0.05 35 3.8 x 4.6 x 10-7
10-6
Pears.......... FT 0.05 50 3.1 x 3.7 x 10-7
10-6
Pecans......... FT 0.10 10 4.8 x 5.8 x 10-9
10-8
Plums.......... FT 0.10 12 7.4 x 8.9 x 10-8
10-7
Poultrymeat.... R 0.0003 - 1.5 x 1.8 x 10-8
10-7
Redmeat........ R 0.0001 - 2.3 x 2.8 x 10-8
10-7
Strawberries... FT 0.05 100 1.8 x 2.2 x 10-7
10-6
Walnuts......... FT 0.10 50 2.4 x 2.9 x 10-8
10-7
------------------------------------------------------------------------
Total 1.1 x 10-5
(excluding
cancelled
uses)\1\.
Total 1.4 x 10-5
(including
cancelled
uses).
------------------------------------------------------------------------
\1\ Voluntarily cancelled uses include sugarcane, artichokes, asparagus
and fish.
3. Cyanazine cancer risk estimates. The total estimated cyanazine
dietary risk from all commodities is 2.9 x 10-5. (Ref. 39). The
largest contributor of risk is corn, both through the raw agricultural
commodity itself and through secondary residues in meat, milk, poultry
and eggs resulting from use of corn as a feed item. DuPont has
requested voluntary cancellation for cyanazine use on sorghum, wheat
and fallow cropland (Ref. 40). If cancellation of these uses becomes
final, the total dietary risk will be 2.7 x 10-5. Unlike
atrazine and simazine, for which new residue data may refine dietary
risks, no new residue data are necessary to refine the exposure
estimates. The dietary cancer risk estimates for cyanazine are shown in
Table 3:
Table 3.-- Dietary Cancer Risk Estimates for Cyanazine
------------------------------------------------------------------------
Anticipated Percent Upper Bound
Commodity Residue Crop Exposure Cancer Risk
(ppm) Treated (mg/kg/day) Estimates
------------------------------------------------------------------------
Corn............ 0.12 20 1.2 x 10- 1.2 x 10-5
Cottonseed....... 0.09 5 9.3 x 10- 9.3 x 10-8
8
Milk............ 0.00028 - 1.2 x 10- 1.2 x 10-6
(milk) 6
0.000034
(non-fat
solids)
Poultry and eggs 0.00232 - - 3.1 x 10- 3.1 x 10-6
0.00432\2\ 6
Red meat........ 0.00345 - - 1.0 x 10- 1.0 x 10-5
0.0103\1\ 5
Sorghum.......... 0.10 5 1.2 x 10- 1.2 x 10-7
7
Wheat........... 0.16 1 2.3 x 10- 2.3 x 10-6
6
------------------------------------------------------------------------
Total.......... 2.9 x 10-5
------------------------------------------------------------------------
\1\ Range of values were used for meat, meat byproducts, fat, liver and
kidney.
\2\ Range of values were used for meat, meat byproducts, fat, liver,
kidney and eggs.
VI. Triazines Exposure in Drinking Water
A. Safe Drinking Water Standards--Health Advisory Levels and Maximum
Contaminant Levels
To ensure public health and safety, EPA is responsible for
establishing protective standards that limit the amount of pesticide
contamination in drinking water. Maximum Contaminant Levels (MCL) are
legally enforceable standards that represent the maximum permissible
level of a contaminant in water delivered to any user of a public water
system. Prior to establishing an MCL, the Safe Drinking Water Act
(SDWA) requires that EPA establish a Maximum Contaminant Level Goal
(MCLG) at the level at which no known or anticipated adverse effects on
the health of persons occur over a lifetime of exposure and which allow
an adequate margin of safety. Health Advisory Levels (HA) are non-
enforceable guidelines that estimate the maximum amount of a
contaminant that can be consumed without causing adverse effects over a
specific period of time. Both the MCLG and the HA, while non-
enforceable, are established as health-based reference points to
provide guidance to ensure the safety of drinking water when an
enforceable standard (MCL) is not available. The National Primary
Drinking Water Regulations Phase II Rule requires water monitoring of
all (60,000) community water systems and all (25,000) nontransient,
noncommunity water systems. Quarterly samples must be taken
consecutively each year. A water supply system is in violation if the
running annual average at any sampling point exceeds the MCL. If the
MCL is exceeded, water systems are required to notify the general
public within 14 days and consumers directly within 45 days.
The MCL for a Group C carcinogen is generally based on the
Reference Dose (RfD) for non-carcinogenic toxic effects. An additional
onefold to tenfold factor is applied to the RfD to account for possible
human carcinogenic effects. The MCL is based on a cancer risk range of
10-5 to 10-6 when non-cancer data are inadequate for deriving
an RfD. EPA has established an MCL for atrazine at 3 g/L (or 3
ppb) and for simazine at 4 g/L (or 4 ppb). EPA expects to
establish an MCL for cyanazine and is also considering the possibility
of setting MCLs for triazine degradates as well as a combination of
triazines.
When monitoring concentrations of contaminants in water supplies,
the contaminant level or the annual average contaminant level is
compared to the MCL established for that contaminant. If any single
maximum contaminant concentration is greater than four times the MCL,
it will automatically make the annual average of four quarterly samples
greater than the MCL. Any water supply system reporting an average of
any four successive quarterly samples greater than the MCL is
considered to be out of compliance with the SDWA. The requirements of
the SDWA do not govern decisions regarding the registrability of
pesticides under FIFRA. However, standards such as MCLs, MCLGs, and HAs
provide useful guidance to the Agency in identifying potential
instances of unreasonable risks. Thus, if a pesticide is found at
levels which exceed one of these levels, it is likely that use of that
pesticide may exceed a Special Review trigger under the FIFRA
regulations. Accordingly, detection of triazine residues in water at or
above these levels is very pertinent to this Special Review.
1. Atrazine Maximum Contaminant Level. The MCL for atrazine of 3
g/L (3 ppb) was established in 1991 (Ref. 41). Based on a
Q1* of 2.2 x 10-1 (mg/kg/day)-1, this MCL is
associated with an estimated cancer risk level within the 10-5
range for drinking water (assuming a person consumes 2 liters of water
per day containing atrazine at 3 g/L over a 70-year lifetime)
The MCL was calculated using the RfD of 0.005 mg/kg/day based on a NOEL
of 0.5 mg/kg/day for decreased body weight in pups in a multi-
generation reproduction study and an additional uncertainty factor of
10 to account for possible human carcinogenic effects. (The RfD was
calculated using an uncertainty factor of 100: 10 for inter-species
extrapolation and 10 for intra-species variability.) To account for
other possible sources of exposure to atrazine, only 20 percent of the
RfD was used to calculate the MCL.
In 1992, the EPA RfD Committee approved an increase in the atrazine
RfD from 0.005 mg/kg/day to 0.035 mg/kg/day, based on evidence of
decreased body weight in a chronic rat study with a NOEL of 3.5 mg/kg/
day (Ref. 42). Based on the increase in the atrazine RfD, the
registrant, Ciba, submitted a petition to the Administrator requesting
a re-evaluation of the MCL and a stay on mandatory requirements
including water monitoring (Ref. 43). The Agency considered, but has
denied Ciba's petition to increase the MCL for atrazine. This denial
takes into account a number of issues concerning the protection of
public health, particularly possible cancer risks from total exposure
to all triazines and their degradates (Ref. 44). The Agency is also
reviewing its carcinogenicity guidelines and the Office of Water is
revising its policy for regulating Category II chemicals which includes
the Group C carcinogens.
2. Simazine Maximum Contaminant Level. In July 1990, an MCL Goal
(MCLG) of 1 g/L (1 ppb) was proposed for simazine based on a
NOEL of 0.5 mg/kg/day for non-carcinogenic toxic effects in a 2-year
rat study. Uncertainty factors applied included a threefold factor to
account for a data gap with respect to the absence of adequate
information to evaluate reproductive effects. This data gap for
simazine was subsequently filled and since no effects were noted at the
dose level (0.5 mg/kg/day) used to calculate the MCLG, the threefold
safety factor was no longer required. Thus, the RfD has been increased
from 0.002 mg/kg/day to 0.005 mg/kg/day. To account for other possible
sources of exposure to simazine, only 20 percent of the RfD was used to
calculate the MCL. An MCL of 4 g/L was established for
simazine (Ref. 45). Based on a Q1* of 1.2 x 10-1 (mg/kg/
day)-1, this value is associated with an estimated cancer risk
level within the range of 10-5 for drinking water (assuming a
person consumes 2 liters of water per day containing simazine at 4
g/L over a 70 year period).
3. Cyanazine Health Advisory. EPA has not yet established an MCL
for cyanazine. In 1988, the Agency established a lifetime Health
Advisory (HA) for cyanazine at 10 g/L (or 10 ppb). Based on a
rat chronic toxicity study submitted to the Agency in 1991 that
indicated cyanazine may cause mammary tumors in female Sprague-Dawley
rats, an additional uncertainty factor of 10 was added to the reference
dose calculations and the HA was changed from 10 g/L to 1
g/L, using an RfD of 0.002 mg/kg/day (decreased body weight
gain and hyperactivity in rats). Based on a Q1* of 1 x 100
(mg/kg/day)-1, this HA is associated with an estimated cancer risk
level from drinking water in the 10-5 range (assuming a person
consumes 2 liters of water per day containing cyanazine at 1
g/L over a 70-year period). To account for other possible
sources of exposure to cyanazine, only 20 percent of the RfD was used
to calculate the HA. The registrant, DuPont, requested that EPA
reconsider the change in the cyanazine HA before establishing an MCL.
DuPont believes that the HA should be based on an 80 percent Relative
Source Contribution rather than 20 percent as used by the Agency. (Ref.
46).
B. Environmental Fate, Chemistry, and Transport of the Triazine
Herbicides
Of the three triazine herbicides, more environmental fate data are
available for atrazine than for cyanazine or simazine simply because of
the high level of atrazine use and the widespread research that has
been conducted with atrazine. The parent triazine compounds as well as
their degradates are expected to leach to ground water and to be
transported to surface waters during runoff events that often occur
after heavy rainfalls. Once the compounds leach into the subsoil and
ground water, metabolism of the triazines slows considerably, because
microbial populations are low and anaerobic conditions are not
uncommon. Therefore, there is a potential for residues to accumulate in
subsoils and ground water after many years of use and pose risks to
humans consuming drinking water from contaminated ground water sources.
When degradate residues are combined with parent residues, estimates of
hazard to humans drinking contaminated drinking water and to aquatic
organisms may be substantially increased.
Atrazine, simazine and cyanazine contain a symmetrical triazine
ring and a chloro group attached to one of the carbons in the ring. The
other two carbons carry substituted amino groups. All three triazines
have an ethyl group on one of the amino groups, but the substituents on
the other amino group differ for each triazine. For atrazine the
substituent contains an isopropyl group and for simazine it is an ethyl
group. For cyanazine, the substituent is a nitrile group that is very
reactive and leads to the formation of degradates containing an amide
and/or a carboxylic acid group. The reactivity of the nitrile group is
reflected in the faster degradation and nature of degradates of
cyanazine when compared to atrazine and simazine.
Based on the Agency's environmental fate data, atrazine and
simazine are likely to be more persistent in water and in soils than
cyanazine; however, all three triazines are mobile in a variety of
soils. The three parent triazines persist in buffered aqueous media (pH
5, 7, and 9) for at least 30 days indicating that abiotic hydrolysis is
not a rapid degradation process for these chemicals. Atrazine and
simazine are resistant to direct photolysis, but photolysis does
contribute to the degradation of cyanazine. In soils incubated under
aerobic conditions, atrazine and simazine have half-lives of 150 and
110 days, respectively, whereas the half-life for cyanazine is 17 to 25
days. Under anaerobic conditions, the half-lives are even longer (about
2 years for atrazine and simazine and 108 days for cyanazine). The
longer half-lives under anaerobic conditions imply that these
herbicides may persist for an extended period of time in ground water
and in oxygen-poor surface waters.
Atrazine and simazine follow similar degradation pathways with both
parent compounds forming hydroxy analogues and des-alkylated chloro
degradates which may persist in soil and water for many months. The
hydroxy degradates tend to be less mobile than parent or des-alkylated
degradates. Unlike atrazine and simazine, cyanazine does not degrade to
a hydroxy analogue, but instead produces degradates containing an amide
and/or a carboxylic acid group formed from the nitrile group. Hydroxy
analogues of these degradates are also formed, but to a lesser extent.
Although cyanazine can produce chloro degradates that are common to
atrazine and simazine, they have been shown to be only very minor
degradation products, at least in laboratory studies.
The parent triazine compounds as well as their degradates
(particularly the chloro degradates) are expected to leach to ground
water and to be transported to surface waters especially during runoff
events that often occur after heavy rainfalls. Because metabolic
processes tend to decrease with increasing anaerobic conditions,
residues of parent compounds and degradates will not break down as
rapidly and will accumulate as the compounds are transported into
deeper soil profiles and ground water or in lakes and reservoirs.
C. Drinking Water Exposure
Drinking water for human consumption may be obtained from both
surface water and ground water sources. Because surface and ground
water sources often are interconnected, contamination of one source may
result in contamination of the other. Data which demonstrate the
presence of the triazines in ground and surface water as well as in
precipitation are discussed in the following sections. In general, the
studies used in the Agency's evaluations were designed to monitor for
specific chemicals and not to estimate populations exposed to them.
It should be noted that EPA is also concerned about potential human
exposure to triazine degradates resulting from consumption of drinking
water. Although limited information is available about their occurrence
in ground and surface water and no MCLs or HAs have been established,
monitoring studies increasingly indicate the presence of triazine
degradates in ground and surface waters in measurable quantities in
many locations.
1. Surface water--a. Surface water monitoring. The Agency has
considered over 15 sets of data on the concentrations of triazine
pesticides in raw and finished surface waters, most of which were
obtained from the 12-state midwestern corn belt where the majority of
the annual triazine use occurs. These data include field monitoring
studies, literature reviews and data submitted under section 6(a)(2),
the provision of FIFRA which requires registrants to inform the Agency
of potentially adverse effects resulting from a pesticide. Information
from 10 monitoring studies and 2 additional submissions of section
6(a)(2) data have been the primary data used in this analysis; the
study-specific sampling characteristics and results of these reports
are summarized in Table 4 (Refs. 47, 48, 49, 50, and 51):
Table 4.--Summary of Surface Water Monitoring Studies
--------------------------------------------------------------------------------------------------------------------------------------------------------
Percentage of
Two highest 90th percentile Median sites with
Percentage of among maximum concentration concentration maximum
Study Sampling Sampling Chemical samples with concentrations of all maximum of all maximum concentrations
locations frequency detections from each detections\1\ detections\2\ equal to or
location (g/L) (g/L) greater than 4
(g/L) times MCL
--------------------------------------------------------------------------------------------------------------------------------------------------------
Smith et al 30 water Weekly April Atrazine 80.3 22.5, 16.3 13 3.57 16.7%
Cyanazine 80.3 6.14, 5.61 4.95 0.59 13.3%
Simazine 80.3% 2.54, 2.23 1.58 0.32
--------------------------------------------------------------------------------------------------------------------------------------------------------
Baker (1988).... 8 Ohio Almost daily Atrazine Not provided 245, 226 48.4 13.6 50.0%
tributaries of April thru for this study
Lake Erie Aug. (1982-
1985)
Cyanazine Not provided 86.1, 23.1 14.9 3.4 40.0%
for this study
Simazine Not provided 10.8, 6.93 4.95 0.78
for this study
--------------------------------------------------------------------------------------------------------------------------------------------------------
Squillace and 6 locations in Approx. monthly Atrazine 91.0% 16, 16 16 7.3 25.0%
Engberg (USGS, Cedar River in May 1985
1988). Basin thru Nov. 1985
Cyanazine 35.0% 8.7, 8.1 8.6 1.8% 41.7%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Roux (Ciba 14 locations in Bimonthly in Atrazine 90.0% 30.5, 30.5 30.1 2.7 17.9%
Geigy, 1988). midwestern late spring
corn belt and early
(rivers/stream summer;
s) monthly at all
other
times(1986-
1987)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Moyer and Cross 30 locations in 4-7 samples per Atrazine: 75.1%
(1988). Illinois location per
(rivers/stream year (1986-
s) 1988)
1986 16, 13 11 3.3 6.67%
1987 24, 18 13 2.3 13.3%
1988 39, 19 3.8 1.0 6.67%
Cyanazine: 75.1%
1986 9, 6.2 5.7 0.66 20.0%
1987 28, 17 11 1.5 13.3%
1988 38, 31 5 0.45 10.0%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Keck (1991) 7 locations in Daily May thru Atrazine Not provided 11.1, 10.7 NA 8.28 0.0%
the Missouri July (1991) for this study
River Basin
Simazine Not provided 0.48, g/L).
Cyanazine 5.6 - 86.1 0.45 - 4.4
Simazine 0.48 - 7 0.07 - 0.78
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Reflects the concentration at which 10 percent of the maximum detections at each sampling location are above and 90 percent are below.
\2\ Reflects the concentration at which 50 percent of the maximum detections at each sampling location are above and 50 percent are below.
The Agency's major findings related to surface water can be
summarized as follows:
\ Of the triazine herbicides, atrazine and cyanazine were detected
most often in both untreated and treated surface water in the
midwestern corn belt. Simazine was detected less often and at lower
concentrations than atrazine and cyanazine in the same region. The
frequency of detects is more likely related to the total amount of each
triazine used rather than a difference in their chemical and physical
properties. The Agency has not received or reviewed any data on the
concentrations of simazine in surface waters which drain areas of heavy
simazine use on orchards and nut trees.
\ Atrazine, atrazine degradates, simazine, and cyanazine residues
often occur in the same water samples at various levels depending on
herbicide usage in that given watershed. The cumulative effects of all
of these triazine compounds on humans from drinking water or on aquatic
and terrestrial ecosystems are assumed to be additive.
\ Atrazine is detected in a high percentage of surface water
samples collected from numerous locations within the corn belt even in
early spring before application and in late fall and winter many months
after application. Cyanazine, and to a lesser extent, simazine, are
detected in a lower but still relatively high percentage of surface
water samples collected during the first couple of months post-
application. However, unlike atrazine, they are generally not detected
in high percentages of samples collected in early spring (pre-
application) or in fall or winter many months after application.
\ After peaking one to several times from early May to early July,
concentrations of atrazine and cyanazine in streams and rivers
typically decline rapidly by late July to August to concentrations less
than 1 g/L and remain at those levels until the application
and post-application periods of the following spring.
\ While most of the available data are on streams and rivers, there
are limited data on lakes and reservoirs. Atrazine, and to a lesser
extent cyanazine, concentrations have been reported to remain elevated
at several g/L almost year round during some years in these
bodies of water in the midwestern corn belt including Hoover Reservoir
in Ohio, Rathbun Reservoir and West Lake in Iowa, Perry and Tuttle
Creek Reservoirs in Kansas and Otter Lake in Illinois. This may be due
at least in part to the resistance of atrazine and cyanazine to abiotic
degradation coupled with low microbiological activities and long
hydrological residence.
\ Results of a number of studies of streams and rivers of the corn
belt indicate that atrazine and cyanazine concentrations
typicallyincrease rapidly from pre-application concentrations of less
than 1 g/L to post-application peak concentrations of at least
several g/L. Peak concentrations frequently exceed 10
g/L and sometimes exceed 20 g/L. Peak concentrations
exceeding 50 g/L appear to be rare, but peak concentrations of
atrazine exceeding 100 g/L (up to 245 g/L) and of
cyanazine exceeding 50 g/L (up to 86 g/L) have been
reported.
\ Peak concentrations generally occur between early May and early
July often in conjunction with or shortly after the first few post-
application runoff events. In areas where tile drainage and/or
groundwater inflow contribute substantially to the loading of atrazine
and cyanazine to surface waters, secondary peaks may occur
substantially after a major runoff event.
\ Peak concentrations of triazines are generally greater in surface
waters draining small watersheds than in those draining large
watersheds, but triazine concentrations tend to remain elevated longer
in surface waters draining large watersheds.
\ Maximum and seasonal-annual time weighted mean concentrations of
atrazine and cyanazine in surface water at the same sampling location
often vary substantially (sometimes > 10X) from year to year depending
in part upon the intensity, duration, and timing of post-application
runoff events.
\ Maximum observed concentrations of simazine in the midwestern
corn belt are less than 4 times its MCL.
\ For atrazine and cyanazine, many of the studies reviewed by the
Agency have significant percentages of sampled locations with several
month to annual means exceeding the atrazine MCL and the cyanazine HA.
However, in many cases where a spring-summer atrazine or cyanazine mean
exceeds the atrazine MCL or cyanazine HA, the annual mean would likely
not exceed the health standard.
\ Contamination of estuarine and marine waters by triazines have
also been reported. Data show that for the period April 1, 1991, to
March 31, 1992, approximately 1.6 percent of the atrazine, 1.6 percent
of the cyanazine, and 2.7 percent of the simazine applied to the
Mississippi River Basin in 1991 were transported to the Gulf of Mexico
(Ref. 52). In a literature review of atrazine in the Chesapeake Bay and
major rivers draining into it, a high percentage of detects (72
percent) were reported in over 600 samples collected from 1976 to 1991,
but only 3 concentrations were greater than 3 g/L (up to 5.9
g/L) (Ref. 53).
b. Triazine degradates in surface water. Atrazine chloro
degradates (desethyl atrazine and deisopropyl atrazine) have been
detected in midwestern stream and river sites at concentrations of an
order or more magnitude less than that of the parent atrazine (Ref.
54). This study suggests that the concentration of atrazine degradates
is generally less than 10 percent of the parent atrazine concentration
in flowing surface water, but may be higher in lakes and reservoirs.
Because they are not typically monitored for, the Agency has no data on
the concentration of the degradates of either cyanazine or simazine in
surface water. It should be noted that atrazine and simazine can
generate two chloro degradates in common. The United States Geological
Survey (USGS) has recently focused on detections of cyanazine in
surface water, but the final report is not yet available.
c. Surface water exposure. The available data suggest that a
number of surface source drinking water supply systems within the corn
belt will have annual average atrazine concentrations exceeding the
atrazine MCL of 3 g/L and/or annual average concentrations of
cyanazine exceeding the cyanazine HA of 1 g/L. Current
estimates may underestimate exposure because they do not include
triazine degradates which could increase exposure levels by 10 percent;
they may overestimate exposure in that they are annual average
concentrations rather than annual time-weighted means. The Agency will
be able to refine estimates of drinking water contamination with
triazines with additional information that will be obtained from
monitoring required by the SDWA. Similarly, the Agency will soon have
access to data on simazine concentrations from recently-begun surface
water monitoring in Florida and California, areas of high simazine use
on fruits and nuts. The SWDA does not currently require water systems
to sample and analyze for cyanazine.
2. Ground water-- a. Ground water monitoring. To evaluate
potential triazine exposure through contaminated ground water, EPA has
reviewed monitoring data that include information submitted to the
Agency by pesticide registrants, States, the USGS as well as
information compiled in the EPA National Pesticide Survey of Drinking
Water Wells (NPS) and studies summarized in OPP's, Pesticides in Ground
Water Database (PGWDB). The Agency's report, Water Resources Impact
Analysis for the Triazine Herbicides, tentatively scheduled for release
late in 1994, describes the studies and summarizes the findings (Ref.
47). A brief description is provided of the major sources of data that
the EPA has used to evaluate exposure to triazine herbicides through
ground water contamination.
The EPA PGWDB (1992) contains data from 153 separate studies with
about 96 percent of the data from wells that serve as sources of
drinking water. The NPS was a statistically designed one-time sampling
of both larger community wells and smaller rural domestic wells
nationwide that are currently used as sources of drinking water. It was
designed to estimate the proportion of wells nationally that contain
pesticides or degradates. The National Alachlor Well Water Survey
(NAWWS) was conducted by the registrant of alachlor, Monsanto, and
contains data from a one-time sampling of private rural wells limited
to alachlor use areas. Estimates of atrazine residues in ground water
can be obtained from the results of this study because alachlor and
atrazine use areas coincide fairly closely; however, this is not the
case with simazine and cyanazine.
A number of States have also initiated ground water monitoring
programs designed to evaluate the impact of pesticides and their
degradates on ground water quality. Among these studies are Iowa's
State-Wide Rural Well Water Survey (SWRL) and Wisconsin's Rural Well
Survey. The Iowa study includes data on atrazine, two chloro degradates
(desethyl atrazine and desisopropyl atrazine) and cyanazine; the
Wisconsin study includes data on atrazine and three chloro degradates
(desethyl atrazine, desisopropyl atrazine, and diamino chlorotriazine).
California's Well Inventory Database is a compilation of reports of any
pesticide testing done on well water in the state. Recently, additional
ground water monitoring has been initiated by Ciba in 22 states.
Preliminary reports indicate that triazine residues have been found in
many drinking water wells nationwide (Ref. 55).
i. Atrazine detections. In OPP's PGWDB, atrazine is the fifth most
often detected pesticide (following aldicarb and its metabolites,
carbofuran, ethylene dibromide and DBCP) with detections in 32 out of
40 states in which samples were collected. Of 1,512 wells that
contained residues of atrazine at the time this data were compiled
(1992), 172 wells (11 percent) were found to have concentrations that
exceed the MCL of 3 g/L. Concentrations ranged from trace
levels to 1,500 g/L.
In the NPS, atrazine was the second most frequently found
pesticide. Based on the data obtained in the NPS, EPA estimated that
atrazine occurred in 70,800 (0.7 percent) rural domestic wells
nationwide and in 1,570 (1.7 percent) community supply wells
nationwide.
Monsanto's NAWWS study was conducted to estimate the proportion of
private, rural domestic wells in the alachlor use area that contain
detectable concentrations of alachlor. Monsanto added four other
herbicides as analytes, including atrazine, simazine and cyanazine.
Atrazine was the most frequently found pesticide and was estimated to
be present in 12 percent of wells in the alachlor use area. Monsanto
estimated that concentrations exceeded the MCL in 0.1 percent of the
wells in the alachlor use area. According to NAWWS data, approximately
12 percent of the population in the alachlor use area (2.4 million
people) is exposed to parent atrazine residues less than 0.2
g/L (0.2 g/L was the limit of detection for atrazine
the study). Approximately 184,000 people in this area are exposed to
residues greater than or equal to 0.2 g/L.
In the state studies reviewed for this Position Document, atrazine
is one of the most frequently detected pesticides. In the Iowa SWRL, it
was the most frequently detected pesticide (4.4 percent of rural
private drinking water wells) and of all pesticides found, atrazine
most often exceeded the MCL. It was estimated that atrazine (parent
only) would be detected in 0.6 percent of wells statewide at
concentrations that exceed the MCL. Additional detections of chloro
triazine degradate increases the total number of wells with detections
and would likely increase the exposure estimates.
In Phase 1 of Wisconsin's ground water study, 218 wells in 45
counties (almost 28 percent) were found to contain detectable (0.1
g/L or greater) triazine residues, predominantly atrazine
parent. Resampling of these well sites for Phase 2 indicated that 49.1
percent of the 236 wells sampled contained atrazine parent at a level
that exceeded the state's Preventive Action Limit of 0.35 g/L.
The State Enforcement Standard of 3.5 g/L was exceeded in 6.4
percent of the wells on the basis of the parent atrazine concentration
alone.
Atrazine is the third most frequently detected pesticide in
California's Well Inventory Database. Confirmed detections resulting
from routine agricultural use have reportedly been found in 119 wells.
Residues of parent atrazine have been reported in 21 counties at
concentrations ranging from 0.02 to 8.5 g/L.
ii. Simazine detections. In OPP's PGWDB, simazine was the eighth
most often detected pesticide with detections reported in 19 out of 30
states in which samples were collected. Of the 486 wells that contained
residues, a total of 36 (7 percent) had concentrations that exceeded
the MCL of 4 g/L. Concentrations ranged up to 67 g/L.
Simazine was also one of the most commonly found pesticides in the
NPS. Based on these data, simazine is estimated to occur in 25,000 (0.2
percent) rural domestic wells and 1,080 (1.1 percent) community supply
wells. The lower percentage of wells with simazine detections compared
to those with atrazine detections is probably due to lower simazine use
in surveyed areas since the two chemicals have a similar potential to
reach ground water.
Monsanto's NAWWS data on simazine estimates that approximately
400,000 people are exposed to at least 0.03 g/L of this
herbicide in ground water, but none at levels above the MCL of 4
g/L. No simazine degradation products were analyzed. Monsanto
states that this may not be a good estimate of simazine occurrence
because the use areas of simazine and alachlor do not closely coincide.
Simazine was the most frequently detected pesticide in California's
Well Inventory Database. Confirmed detections resulting from routine
agricultural use have reportedly been found in 296 wells. Residues of
simazine parent only have been reported in 20 counties at
concentrations ranging from 0.02 to 49.2 g/L. Simazine was not
an analyte in the Iowa State-Wide Rural Well Water Survey or the
Wisconsin Rural Well Survey.
iii. Cyanazine detections. Fewer monitoring data exist for
cyanazine in ground water than for atrazine and simazine. In OPP's
PGWDB, cyanazine was the fifteenth most often detected pesticide with
detections in 15 out of 27 states in which samples were collected. Of
155 wells that contain residues, a total of 22 (14 percent) reported
cyanazine concentrations that exceed the HA of 1 g/L.
Concentrations range from trace levels to 29 g/L.
In Iowa's State-Wide Rural Well Water Survey, cyanazine was the
fifth most frequently detected pesticide out of 27 analytes.
Approximately 1.2 percent of rural private drinking water wells in Iowa
were estimated to be contaminated with cyanazine parent. The maximum
concentration detected was 0.84 g/L.
NAWWS estimates that detectable levels of cyanazine are expected to
occur in 0.3 percent of rural domestic wells in counties where alachlor
is used. As in the case of simazine, these estimates may not be
accurate because the use areas of cyanazine and alachlor do not closely
coincide. However, using this information, OPP estimates that about
60,000 people are exposed to at least 0.1 g/L of cyanazine in
ground water.
No detections of cyanazine were reported in the NPS; however, the
minimum detection limit in that study was high (2.4 g/L) when
compared to the HA of 1 g/L. Cyanazine was not an analyte in
the Wisconsin study. No confirmed detections of cyanazine are reported
in the California database.
iv. Triazine degradates in ground water. Only limited information
is available on the occurrence or level of triazine degradates in
ground water. Data on cyanazine degradates, in particular, are rarely
sought. The most significant information on degradation products comes
from the Iowa and Wisconsin state surveys, and from a ground water
reconnaissance study conducted by the USGS. In contrast with the levels
of degradates found in rivers and streams (up to 10 percent of the
level of the parent), levels of the degradates in ground water can be
much more significant; total triazine concentrations in ground water
can double or triple, when chloro degradates and parent are both
considered.
In the Iowa State-Wide Rural Well Water Survey, two of the three
major chloro degradates of atrazine, desethyl and desisopropyl, were
both detected at approximately the same rate (3.5 percent and 3.4
percent, respectively) as atrazine parent (4.4 percent). Degradates
were commonly detected in combination with atrazine, but over half of
the metabolite detections occurred when atrazine parent was not
present. Because of the incidence of detections of triazine degradates,
the percentage of wells that were found to contain triazine residues
approximately doubled from 4.4 percent (atrazine alone) to 8 percent
(total triazine residues) when comparing parent only detects with
parent plus degradate detects.
In the Wisconsin Rural Well Survey, degradates accounted for 67
percent of total triazine residues detected. Almost 92 percent of wells
that were resampled in Phase 2 of the study contained a combination of
parent and degradate residues. Two atrazine chloro degradates, desethyl
atrazine and di-amino s-triazine, were found with approximately the
same frequency as atrazine parent (83 to 88 percent) at concentrations
of up to 8.8 and 9.9 g/L, respectively. A third chloro
degradate, desisopropyl atrazine, was detected less frequently (60.6
percent) and at lower concentrations (0.1 to 2.6 g/L). As
discussed previously, atrazine parent concentrations exceeded the
Wisconsin enforcement standard in 6.4 percent of the wells, while
combined concentrations of atrazine and chloro degradates exceeded the
State Enforcement Standard (ES) in 29 percent of the wells resampled,
or 3 percent more than the number of original wells exceeding the ES.
Preliminary results of a recent USGS study of herbicides and
nitrates in near-surface aquifers in the midcontinental United States
indicate that the degradate desethyl atrazine was the most frequently
reported compound (18.1 percent of wells), followed by atrazine (17.4
percent) and desisopropyl atrazine (5.7 percent) (Ref. 56).
Approximately 25 percent more wells contained total triazine residues
than wells in which atrazine parent alone was found. No analyses were
done for the third chloro degradate, diamino chlorotriazine. This study
differs from the NPS and NAWWS studies in that it was not statistically
designed, and it sampled ground water, not just ground water used as a
source of drinking water.
b. Ground water exposure. The triazine chemicals have had a major
impact on ground-water resources. In atrazine use areas, ground-water
contamination is widespread at levels well below the Maximum
Contaminant Level, but occurs at higher levels in localized areas. This
contamination may persist for decades or longer in ground water. With
currently available analytical methodology, atrazine is the most
frequently detected pesticide in ground water in the midwestern United
States, including Nebraska, Iowa, Illinois, Indiana, Minnesota, and
Wisconsin. The Pesticides in Ground Water Database 1992 Report
indicates that atrazine has been detected in 32 out of the 40 states
that have reported monitoring data. EPA estimates that, based on
results of the NPS and the NAWWS, between 2 million and 3 million
people using ground water as their primary drinking water source are
exposed to atrazine at average concentrations of at least 0.2
g/L. S-triazine herbicides other than atrazine (simazine,
cyanazine, and prometon) have had much less cumulative impact on
ground-water quality than atrazine, probably because they are less
intensively used. Another important factor leading to this conclusion
is that they have not been as extensively studied. Recent information
also indicates that at least three triazine metabolites can constitute
a significant component of the total residues in ground water. The
impact on ground water quality and human health from these metabolites
is still unknown, but there is the potential that these compounds could
contribute to the toxic effects on humans and the environment. In
addition, since surface water and shallow ground water are often
hydraulically connected, rivers contaminated with s-triazines can
contaminate nearby wells; alternatively, contaminated ground water can
supply water to rivers.
The USGS has recently focused on detections of cyanazine degradates
in groundwater. However, a final report has not yet been published.
According to the NAWWS data, approximately 12 percent of the population
in the alachlor use area (2.4 million people) are exposed to atrazine
residues of less than 0.2 g/L. Approximately 184,000 people in
this area are exposed to residues greater than or equal to 0.2
g/L (limit of detection for the study). Monsanto's NAWWS data
on simazine estimates approximately 400,000 people are exposed to at
least 0.03 g/L of this herbicide in ground water, but none at
levels above the MCL of 4 g/L. Using the NAWWS data on
cyanazine, OPP estimates that about 60,000 people are exposed to at
least 0.1 g/L in ground water. As mentioned earlier, the
exposure numbers for simazine and cyanazine may not be good estimates
because the use areas of these chemicals do not closely coincide with
those of alachlor.
D. Triazines in Precipitation
Triazines are also found in precipitation. These residues in
rainfall are expected to be additive to the triazine residues already
found in surface water. Therefore ``triazine rainfall'' reaching
surface water may also increase the levels of contamination in drinking
water. Triazine herbicides have been detected in precipitation samples
in a study of 23 states in the upper midwest and northeast United
States (Ref. 57). Atrazine was the most frequently detected herbicide,
followed by alachlor, desethyl atrazine and metolachlor. Concentrations
ranging from 1 to 3 g/L of atrazine were measured in a few
samples; however, most precipitation-weighted herbicide concentrations
varied between 0.2 and 0.4 g/L in May and June samples.
Another study conducted in Isle Royale National Park, Michigan, showed
that rainwater samples contained atrazine residues ranging from trace
levels to 0.05 g/L (Ref. 58). Atrazine residues ranging up to
1.5 g/L were also detected in rainwater in the rural areas of
Iowa with large variations in the pesticide content of precipitation
between individual storms (Ref. 59).
VII. Risks from Exposure to Triazine-Contaminated Drinking Water
A. Risk Estimates at the Maximum Contaminant Level/Health Advisory
Triazines pose a potential drinking water risk to exposed human
populations. Monitoring data indicate that there is extensive triazine
contamination of ground water and surface water used for drinking
purposes. The estimates of the levels of exposure would be expected to
increase if complete monitoring data were available for the degradates.
The extent of the human population exposed to these contaminated
drinking water sources (i.e. exposure greater than the MCL) is not
certain. However, 29 million people use surface water for drinking
water in 11 corn belt states with the remainder of the people using
ground water for drinking purposes.
As stated previously, EPA has established MCLs for atrazine and
simazine at 3 g/L and 4 g/L, respectively, and an HA
for cyanazine at 1 g/L. When establishing MCLs, the Agency
assumes a Relative Source Contribution (RSC) of at least 20 percent in
the drinking water and 80 percent from other sources. (The RSC refers
to the percentage of the RfD allocated to a particular source, i.e.
water contributes 20 percent of the total exposure). As yet, there are
no MCLs established for triazine degradates and estimates of risk from
consuming water contaminated by the triazine herbicides do not include
the potential risks associated with exposure to their degradates.
Estimating carcinogenic risk from drinking water assumes lifetime (70
years) consumption of 2 liters of water per day by a 70 kg human.
Based on the cancer potency (Q1*) and exposure (i.e. 2 L/day)
assumptions used to calculate carcinogenic risk, exposure to atrazine
in drinking water at the MCL (3 g/L) results in an upper bound
excess carcinogenic risk of 1.9 x 10-5. Exposure to simazine in
drinking water at the MCL (4 g/L) results in an upper bound
excess carcinogenic risk of is 1 x 10-5. Exposure to cyanazine
in drinking water at the HA (1 g/L) results in an upper bound
excess carcinogenic risk of 2.5 x 10-5.
B. Risk Estimates Based on Monitoring Data
Drinking water risks from ground or surface water sources are not
typically included in EPA's estimates of dietary (food) risk due to
lack of adequate monitoring data, fluctuations in exposure levels
geographically, poor consumption information and other factors. Since
there are surface and ground water monitoring data available for the
triazines, these data have been used to develop more realistic
estimates of triazine drinking water risks to exposed populations.
However, data are not available to allow OPP to determine the number of
people who actually consume surface water contaminated with the
triazines.
1. Surface water sources. To estimate risks from surface water
exposure, two monitoring studies were considered. The first study
monitored for 15 pesticides, including atrazine and cyanazine, in
surface water at 30 stations (flowing water) in Illinois (Ref. 60).
Because the Illinois study did not sample for simazine, a second study
that was conducted primarily to provide information on the occurrence
of alachlor in drinking water, but also monitored atrazine, simazine
and cyanazine, was used to determine the average time-weighted mean
concentrations (TWMC)(averages over 30 supplies) for simazine. The
average TWMCs are 0.84 g/L for atrazine, 0.23 g/L for
simazine and 0.43 g/L for cyanazine; the high end or 90th
percentile TWMCs are 1.88 g/L for atrazine, 0.31 g/L
for simazine and 1.66 g/L for cyanazine. The Agency estimated
exposure for mean tapwater intake and 90th percentile consumption using
values of 22.6 and 39.8 g water/kg bwt/day, respectively. Consumption
values were derived from USDA's 1977-78 Nationwide Food Consumption
Survey (Ref. 61). The use of this water consumption value may
underestimate risk because it does not include consumption of
``commercial water'' added during the manufacture and processing of
products such as sodas and beer. The excess individual lifetime cancer
risk estimates from both average and 90th percentile exposure to
triazines in surface water are shown in Table 5 (Ref. 60):
Table 5.--Excess Individual Lifetime Cancer Risk Estimates from
Consumption of Surface Water
------------------------------------------------------------------------
Mean Exposure 90th Percentile
------------------------------------------------------------------------
Atrazine............... 4.2 x 10-6 1.6 x 10-5
Simazine............... 6.2 x 10-7 1.5 x 10-6
Cyanazine.............. 9.7 x 10-6 6.6 x 10-5
------------------------------------------------------------------------
It is important to note that these cancer risk estimates for
surface water are geographically restricted and do not apply to the
entire U.S. population, but are representative values for individuals
residing in the corn belt region. In other regions of the country where
the triazines are not used, there will be no risk from drinking water,
while in some areas (i.e., Florida and Central Valley of California)
simazine concentrations are likely to be much higher than in the corn
belt.
2. Ground water sources. To estimate risks from ground water
exposure, detections from NAWWS monitoring data were used with the same
drinking water intake assumptions discussed earlier for surface water.
The NAWWS data provide the best estimates of exposure based on
currently available ground water information.
Assuming Q1*s of 2.2 x 10-1 (mg/kg/day)-1 for
atrazine; 1.2 x 10-1 (mg/kg/day)-1 for simazine; and 1.0
x 100 (mg/kg/day)-1 for cyanazine, the upper bound excess
individual lifetime cancer risk estimates for the triazines are
provided in Table 6 (Ref. 62):
Table 6.--Excess Individual Lifetime Cancer Risk Estimates from
Consumption of Ground Water
------------------------------------------------------------------------
Mean Exposure 90th Percentile
------------------------------------------------------------------------
Atrazine............... 9.9 x 10-7 1.8 x 10-6
Simazine............... 8.1 x 10-8 1.4 x 10-7
Cyanazine.............. 2.3 x 10-6 4.0 x 10-6
------------------------------------------------------------------------
Because these estimates apply only to those individuals consuming
triazine-containing drinking water from rural domestic wells in the
alachlor use area, they may underestimate risk. In addition, because
the NAWWS residue values used to estimate risk are lower bound
estimates, cancer risks may be higher. Furthermore, it is important to
note that the exposure estimates from the NAWWS data do not include
triazine degradates; their inclusion could increase the exposure
estimates, thereby increasing the risk.
C. Registrants' Responses to Preliminary Notification Concerning
Drinking Water Risks and Agency Comments
Ciba and DuPont have responded to the Agency's preliminary
notification of possible Special Review for drinking water risks
associated with triazine contamination. The registrants' responses and
the Agency's comments are detailed below.
In DuPont's response, it stated that a voluntary cyanazine exposure
reduction program proposed in 1993 was developed in close cooperation
with the Agency and that the program is aimed at reducing ground and
surface water contamination with cyanazine from agricultural point and
non-point sources. DuPont developed the risk reduction program to
address Agency concerns regarding surface water detections in
exceedance of the current cyanazine HA of 1 g/L resulting from
rainfall run-off events. DuPont contends that their program will
significantly reduce runoff contamination of drinking water supplies. A
report on the effectiveness of the risk reduction measures will be
available to the Agency in the Fall of 1994.
The Agency believes that DuPont's 1993 proposal was a positive step
towards reducing ground and surface water contamination, but clearly
indicated when accepting the proposal that these were considered to be
only interim measures. The Agency has no information that shows that
these risk reduction measures have reduced contamination to an
acceptable level. During the Special Review, the Agency will evaluate
the report that DuPont will submit and determine the effectiveness of
these measures and whether or not additional measures will be
necessary.
The Agency remains concerned about the occurrence of cyanazine at
exceedances of its HA in ground water. Both ground water and surface
water supplies serve as sources for drinking water and are often
interconnected. Data from the Pesticides in Ground Water Data Base
estimated that approximately 57 surface water systems exceeded the HA
compared with about 360 ground water systems. Although some ground
water systems may be influenced by surface water, and may show lower
levels of cyanazine as a result of mitigation measures, the Agency is
still concerned that most ground water systems would remain vulnerable
to contamination from cyanazine leaching. Furthermore, the contribution
of cyanazine degradates to the total triazine residue in both surface
and groundwater is still unknown because no published data on cyanazine
degradate monitoring are available at the present time. However, the
Agency is aware of ongoing research by the USGS in this area and will
evaluate all new information as it becomes available (Ref. 56).
DuPont also stated that it believed that the HA for cyanazine
should be increased and has petitioned the Office of Water to
reevaluate and raise the HA based upon an 80 percent Relative Source
Contribution (RSC) from water.
In April 1994, the Agency denied DuPont's request to change the RSC
used in deriving the cyanazine HA. The Agency believes that it is
prudent to use a 20 percent RSC value rather than 80 percent for the
following reasons: (1) the Agency RSC workgroup is still discussing
multimedia exposure and the allocation of the RSC from drinking water,
and (2) there are uncertainties associated with the contribution of
total triazines and their degradates to the total exposure. (Ref. 63).
Ciba contends that, based on currently available health and safety
data for atrazine and simazine, no significant health risks result from
exposure to contaminated drinking water. Ciba also states that it has
designed and implemented a 22-state ground water monitoring program to
define the presence of atrazine, simazine and their chloro metabolites
in water. Ciba believes that most water supply systems can comply with
a MCL of 3 g/L for atrazine but that some systems will be
above the standard at some times during any given year, and in some
cases, on an annual basis. Ciba petitioned the Agency to reevaluate the
MCL for atrazine based on the revised RfD established for atrazine on
October 1, 1993, citing the increase in the RfD as the basis. Ciba also
claimed an inconsistency in the Agency's views regarding water systems
exceeding the established MCL. Ciba recounted that during a meeting
with the Office of Water, there was no urgency on behalf of the Agency
to revise the MCL because water utilities nationally would not have a
problem complying with the current standard. Ciba points out that, on
the other hand, the Agency has issued the preliminary notification
because of concern for compliance with the current standard. For
simazine, Ciba believes the current monitoring data demonstrate that
widespread contamination of drinking water does not exist and that
results of the ongoing program will support this position.
The Agency has reviewed Ciba's position and has a number of
comments. The positions of the Office of Water and the Office of
Pesticide Programs are not inconsistent in that both are concerned
about health risks from drinking water and both offices have chosen to
take a position most protective of public health. As discussed
previously, the Agency recently has denied Ciba's request to revise the
MCL for atrazine. For both atrazine and simazine, the Agency is
initiating this Special Review because of data that show levels of
ground and surface water contamination which could result in
unacceptable drinking water risks.
VIII. Triazine Non-dietary Exposure and Risks
Occupational and residential exposure to atrazine, simazine and
cyanazine varies depending on several factors including the use
pattern, the specific crop treated, the personal protective equipment
used, whether the person exposed is a grower or commercial applicator,
whether an individual is mixing, loading or applying the pesticide, and
whether the individual is a homeowner. In general, a grower is likely
to be involved in all aspects of the pesticide treatment, while in
commercial operations, different individuals usually mix/load and apply
the pesticide. The total exposure to growers is generally lower than
for commercial operators because growers usually treat fewer acres, use
less pounds of active ingredient per season and are exposed for only a
few days each year. The Agency has estimated only dermal exposure to
workers and residents because inhalation exposure for the triazines is
negligible in comparison to dermal exposure.
A. Triazine Non-Dietary Exposure and Carcinogenicity Risk
1. Exposure assumptions-- a. Atrazine. The Agency has estimated
exposure for mixer/loaders; aerial, ground boom and handheld spray gun
applicators; and aerial flaggers at representative use sites. The use
sites chosen because they represent major atrazine uses are corn,
sorghum and sugarcane. Macadamia nut orchards are selected to represent
handheld spray gun applications and turf uses are selected to represent
home gardener uses.
In determining the exposure estimates for the representative
atrazine use sites, it is assumed that all pesticide handlers wear long
sleeve shirts, long pants and boots, but only mixer/loaders wear
chemical resistant gloves. Exposure to mixer/loaders is estimated
assuming an open pour system or a closed loading system. For ground
boom application to corn, sorghum and sugarcane, exposure to
applicators using an open cab is distinguished from that of applicators
using closed cab equipment; however, currently registered labels do not
require closed loading nor closed cab tractors. Atrazine exposure
estimates for agricultural crops were derived using an application rate
of 1.0 or 1.2 lbs. active ingredient/acre.
The Agency has considered a recent exposure study submitted by Ciba
that monitored dermal and inhalation exposure to mixer/loaders and
applicators during commercial and homeowner turf treatment using
products containing atrazine. This exposure monitoring study
characterized exposure for four different scenarios, including: (1)
home use lawn treatment using a ``Push Cyclone Spreader''; (2) home use
lawn treatment with a hand cyclone spreader; (3) mixing/loading and
``handgun'' application to client lawns by a pest control operator
(PCO); and (4) mixing/loading and ``handgun'' spray application to a
golf course by a golf course caretaker. To estimate exposure to
homeowners and PCO/golf course caretakers, application rates of 3.17
and 3.96 lbs. active ingredient/acre, respectively, were used.
b. Simazine. Dermal exposure estimates for agricultural workers
exposed to simazine are based on the same assumptions as those
discussed above for atrazine. Exposure estimates from open or closed
loading systems, open or closed cab tractors, or from use of aerial
equipment are used to estimate the cancer risk from occupational
exposure. Simazine estimates are based on an application rate of 1.1
lb. active ingredient/acre.
c. Cyanazine. The Agency has derived exposure estimates for corn,
the predominant cyanazine use site. These estimates are based on
assessments completed for atrazine because both pesticides are used and
applied to field corn in a similar fashion. The cyanazine estimates are
based on an application rate of cyanazine alone at 3 lb. active
ingredient/acre.
2. Non-dietary cancer risk estimates. Excess individual lifetime
cancer risk estimates for agricultural workers are calculated from the
following equation:
Cancer risk = Q1* x LADE x percent dermal absorption
where LADE = exposurex (mg/kg/yr)/365 days/yr x 35/70 = lifetime
average daily exposure.
For home use and commercial application to turf, the cancer risks are
estimated from the following equation:
Cancer risk = Q1* x LADD (lifetime average daily dose)
where LADD = (Dermal LADE x percent dermal absorption) +
Inhalation LADE
a. Atrazine. To estimate cancer risk for atrazine, the Agency used
a dermal absorption value of 26.9 percent derived from a rat dermal
absorption study. Based on this dermal absorption value, upper bound
excess individual lifetime cancer risks range from 10-6 to
10-2 for individuals involved in the agricultural application of
atrazine as shown in Table 7 (Ref. 64):
Table 7.-- Atrazine - Occupational Cancer Risk Estimates for Agricultural Crops
----------------------------------------------------------------------------------------------------------------
Crop/Application Daily Exposure (mg/kg/ Annual Exposure (mg/ Upper Bound Cancer
Method Tasks day) kg/yr) Risk Estimates\1\
----------------------------------------------------------------------------------------------------------------
Corn - Grower/Ground M/L - open 1.78 3.11 2.5 x 10-4
M/L - closed 0.029 0.05 4.0 x 10-6
A - open 4.96 8.65 7.1 x 10-4
A - closed 0.19 0.34 2.8 x 10-5
M/L/A - open/open 6.74 11.76 9.5 x 10-4
M/L/A - open/closed 1.97 3.45 2.8 x 10-4
M/L/A - closed/open 4.99 8.70 7.1 x 10-4
M/L/A -closed/closed 0.22 0.39 3.1 x 10-5
Corn - Commercial/ M/L - open 6.38 95.66 7.7 x 10-3
Ground boom.
M/L - closed 0.10 1.54 1.2 x 10-4
A - open 5.15 77.76 6.5 x 10-3
A - closed 0.20 3.02 2.4 x 10-4
M/L/A - open/open 11.53 173.42 1.4 x 10-2
M/L/A - open/closed 6.58 98.68 8.3 x 10-3
M/L/A - closed/open 5.25 79.30 6.5 x 10-3
M/L/A -closed/closed 0.30 4.56 3.7 x 10-4
Corn - Commercial/ M/L - closed 0.099 1.49 1.2 x 10-4
Aerial.
Pilot 0.008 0.12 9.5 x 10-6
Flagger 0.044 0.66 5.3 x 10-5
Sorghum - Grower/ M/L - open 1.42 1.79 1.5 x 10-4
Ground boom \2\.
M/L - closed 0.023 0.029 2.4 x 10-6
A - open 4.8 5.99 4.9 x 10-4
A - closed 0.19 0.23 1.9 x 10-5
M/L/A - open/open 6.22 7.78 6.5 x 10-4
M/L/A - open/closed 1.61 2.02 1.7 x 10-4
M/L/A - closed/open 4.82 6.02 4.9 x 10-4
M/L/A - closed/closed 0.21 0.26 2.1 x 10-5
Sugarcane - Ground M/L - open 5.31 80.0 6.5 x 10-3
boom (Commercial).
M/L - closed 0.086 1.3 1.1 x 10-4
A - open 4.29 64.2 5.2 x 10-3
A - closed 0.17 2.49 2.0 x 10-4
M/L/A - open/open 9.60 144.2 1.2 x 10-2
M/L/A - open/closed 5.48 82.49 6.5 x 10-3
M/L/A - closed/open 4.38 65.5 5.3 x 10-3
M/L/A -closed/closed 0.26 3.79 3.1 x 10-4
Sugarcane - Aerial... M/L - closed 0.094 2.8 2.2 x 10-4
Pilot 0.007 0.22 1.8 x 10-5
Flagger 0.041 1.23 1.0 x 10-4
Macadamia nuts - M/L - open 0.79 3.2 2.6 x 10-4
Handheld sprayer\2\.
A - single applicator 16.84 67.4 5.4 x 10-3
A - split application 16.84 33.7 2.7 x 10-3
M/L/A - single app. 17.63 70.6 5.7 x 10-3
M/L/A - split app. 17.63 36.9 3.0 x 10-3
----------------------------------------------------------------------------------------------------------------
\1\ Based on potential dermal absorption of 26.9%.
\2\ Exposure is only 1 to 4 days per year.
Because growers are likely to be involved in mixing, loading and
applying atrazine, it is important to consider the total exposure from
all of these operations. In commercial operations, different
individuals are likely to mix/load and apply atrazine. The occupational
cancer risk estimates for atrazine are primarily dependent upon whether
mixer/loaders use open versus closed loading systems, and whether
application occurs from open versus closed cab equipment. As stated
previously, currently approved labels do not require closed equipment.
In addition, cancer risk estimates vary depending on the method of
application.
The Agency estimates the upper bound excess individual lifetime
cancer risks for residents loading and applying atrazine to home lawns
to range from 10-6 to 10-5. For PCO treatment of turf, cancer
risk estimates are in the range of 10-3 for mixer/loaders,
applicators and mixer/loader/applicators. The cancer risk estimates for
treatment of golf courses by golf course caretakers are 10-5 for
both mixer/loaders and applicators, while the cancer risk to those
performing all three tasks is 10-4. These estimates are shown in
Table 8 (Ref. 65):
Table 8.-- Atrazine - Occupational Cancer Risk Estimates for Turf/Lawns
--------------------------------------------------------------------------------------------------------------------------------------------------------
Daily Dermal Daily Inhalation Annual Dermal Annual Inhalation
Application Method Tasks Exposure\1\ (mg/kg/ Exposure\1\ (mg/kg/ Exposure\1\(mg/kg/ Exposure\1\(mg/kg/ Upper Bound Cancer
day) day) yr) yr) Risk Estimates\2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Home Use - Push M/L/A 0.045 0.0002 0.045 0.0002 3.7 x 10-6
Home Use - Hand M/L/A 0.285 0.0008 0.285 0.0008 2.4 x 10-5
Cyclone Spreader\3\.
PCO - Handgun M/L 0.217 0.016 11.593 0.878 1.2 x 10-3
Application.
A 0.282 0.004 15.106 0.211 1.3 x 10-3
M/L/A 0.499 0.020 26.699 1.088 2.5 x 10-3
Golf Course - M/L 0.739 0.056 0.739 0.056 7.7 x 10-5
Handgun Application.
A 1.702 0.069 1.702 0.069 1.6 x 10-4
M/L/A 8.311 0.336 8.311 0.336 7.8 x 10-4
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Assumes 70 kg worker.
\2\ Based on potential dermal absorption of 26.9% and potential inhalation absorption of 100%.
\3\ Gloves were not worn.
b. Simazine. To estimate cancer risk for simazine, the Agency used
a dermal absorption value of 32 percent derived from a rat dermal
absorption study. Based on this dermal absorption value, estimated
upper bound cancer risks to individuals involved in the application of
simazine to field corn range from 10-6 to 10-2 (Ref. 64).
Occupational cancer risks are comparable to those of atrazine because
both pesticides are applied using similar equipment and application
rates. The occupational cancer risks from exposure to simazine are
provided in Table 9:
Table 9.--Simazine - Occupational Cancer Risk Estimates
----------------------------------------------------------------------------------------------------------------
Crop/Application Daily Exposure (mg/kg/ Annual Exposure (mg/ Upper Bound Cancer
Method Tasks day) kg/yr) Risk Estimates\1\
----------------------------------------------------------------------------------------------------------------
Corn - Grower/Ground M/L - open 1.61 2.86 1.5 x 10-4
boom
M/L - closed 0.026 0.046 2.4 x 10-6
A - open 4.54 7.93 4.2 x 10-4
A - closed 0.18 0.31 1.6 x 10-5
M/L/A - open/open 6.15 10.79 5.8 x 10-4
M/L/A - open/closed 1.79 3.17 1.7 x 10-4
M/L/A - closed/open 4.57 7.98 4.2 x 10-4
M/L/A - closed/closed 0.21 0.36 1.9 x 10-5
Corn - Commercial/ M/L - open 5.85 87.7 4.6 x 10-3
Ground boom
M/L - closed 0.094 1.41 7.3 x 10-5
A - open 4.72 71.3 3.8 x 10-3
A - closed 0.18 2.77 1.5 x 10-4
M/L/A - open/open 10.57 159.0 8.4 x 10-3
M/L/A - open/closed 6.03 90.47 4.6 x 10-3
M/L/A - closed/open 4.81 72.71 3.8 x 10-3
M/L/A - closed/closed 0.27 4.18 2.2 x 10-4
Corn - Commercial/ M/L - closed 0.091 1.36 7.3 x 10-5
Aerial
Pilot 0.007 0.11 5.8 x 10-6
Flagger 0.04 0.60 3.1 x 10-5
----------------------------------------------------------------------------------------------------------------
\1\ Based on potential dermal absorption of 32%.
c. Cyanazine. To estimate cancer risk for cyanazine, the Agency
used a dermal absorption value of 2 percent derived from a rat dermal
absorption study. Based on this dermal absorption value, the
occupational cancer risks to individuals involved in the application of
cyanazine to field corn range from 10-6 to 10-2 (Ref. 64).
The results are comparable to those of atrazine and simazine and are
provided in Table 10:
Table 10.--Cyanazine - Occupational Cancer Risk Estimates
----------------------------------------------------------------------------------------------------------------
Crop/Application Daily Exposure mg/kg/ Annual Exposure (mg/ Upper Bound Cancer
Method Tasks day) kg/yr) Risk Estimates\1\
----------------------------------------------------------------------------------------------------------------
Corn - Grower/Ground M/L - open 4.46 7.77 2.2 x 10-4
boom.
M/L - closed 0.072 0.13 3.6 x 10-6
A - open 12.39 21.63 6.0 x 10-4
A - closed 0.48 0.84 2.4 x 10-5
M/L/A - open/open 16.85 29.40 8.0 x 10-4
M/L/A - open/closed 4.94 8.61 2.4 x 10-4
M/L/A - closed/open 12.46 21.76 6.0 x 10-4
M/L/A - closed/closed 0.55 0.97 2.6 x 10-5
Corn - Commercial/ M/L - open 15.94 239.1 6.6 x 10-3
Ground boom.
M/L - closed 0.26 3.86 1.1 x 10-4
A - open 12.88 194.4 5.4 x 10-3
A - closed 0.50 7.54 2.0 x 10-4
M/L/A - open/open 28.82 433.50 1.2 x 10-2
M/L/A - open/closed 16.44 246.64 6.8 x 10-3
M/L/A - closed/open 13.14 198.26 5.4 x 10-3
M/L/A - closed/closed 0.76 11.40 3.2 x 10-4
Corn - Commercial/ M/L - closed 0.25 3.71 1.0 x 10-4
Aerial.
Pilot 0.02 0.30 8.2 x 10-6
Flagger 0.11 1.65 4.6 x 10-5
----------------------------------------------------------------------------------------------------------------
\1\ Based on potential dermal absorption of 2%.
B. Triazine Non-Dietary Exposure and Cardiotoxicity Risks (Atrazine
Only)
1. Cardiotoxicity risk exposure assumptions. As discussed in Unit
III of this notice, the Agency used a NOEL of 5.0 mg/kg/day to
characterize cardiotoxicity risk to workers from exposure to atrazine.
Because this NOEL was derived from an oral feeding study, and the
primary route of exposure to workers is via dermal contact, the Agency
accommodated for this difference by using kinetic data which allowed a
comparison of peak blood concentration data from oral toxicity and
dermal absorption studies (Ref. 66). Comparing the blood concentrations
following administration by different routes represents a more accurate
method of assessing exposure and ultimately risk because it accounts
for absorption, distribution and excretion, which can be different
depending upon the route of administration. The data showed that
maximum blood levels following dermal exposure were several orders of
magnitude lower than those following ingestion of the chemical at
similar doses.
2. Margins of exposure (MOE) for cardiotoxic risk. The Agency
generally considers an MOE of 100 or greater to be adequately
protective for workers. The Agency calculated MOE values by comparing
daily exposure estimates against a NOEL of 5.0 mg/kg/day for
cardiotoxicity. Using the revised NOEL of 5.0 mg/kg/day and the kinetic
data, the MOEs for workers functioning as mixer/loaders and applicators
are greater than 100 for all use scenarios, thereby alleviating the
Agency's concerns of cardiotoxic effects for workers exposed to
atrazine (Ref. 65).
IX. Combining Cancer Risks Across Exposure Pathways and Chemicals
In June, 1993, the National Academy of Sciences released a report
entitled ``Pesticides in the Diets of Infants and Children.'' The
report, requested in 1988 by the U.S. Congress, made specific
recommendations for changes in pesticides regulatory practice,
including the area of risk assessment methodology. The Academy
recommended that EPA evaluate potential risk from exposure to several
pesticides with common mechanisms of action and/or exposure via
multiple routes. These recommendations are, in fact, long standing
directives of the law governing the tolerance setting process, as set
forth in the Federal Food, Drug and Cosmetic Act. Section 408 of the
Act specifically states that appropriate consideration is to be given
``...to other ways in which a consumer might be affected by the same
pesticide chemical or by related substances that are poisonous or
deleterious...'' The Agency is implementing these recommendations using
a phased-in approach, beginning with a few case studies for which
information already exists to establish a commonality of mechanism. For
assessments involving multiple routes of exposure, case studies will
also be conducted. These studies will evaluate potential cumulative
exposures resulting from a single chemical which has many food uses as
well as domestic and commercial non-food uses. An example of the
ultimate implementation of these recommendations would be a case study
for a chemical class which appears to share a commonality of mechanism
of action and is registered for use on many food, nonfood and
residential sites. In the coming years, substantial discussion,
research and generation of data will be needed to reach agreement both
on what is meant by ``common mechanisms of action'' and appropriate
methods for estimating risks to subpopulations from multiple routes of
exposure.
The Agency has selected the triazines as a candidate for one of the
case studies. This selection was based on a number of factors. This
group of pesticides presents an example where a plausible argument can
be made for supporting the assumption that atrazine, simazine and
cyanazine operate through a common mechanism of action for the
carcinogenic response observed in the rat mammary gland. In addition,
treatment of various commodities with atrazine, simazine and cyanazine
results in the presence of common metabolites, some of which are of
toxicological significance. From an exposure standpoint, the triazines
are used on a variety of food and non-food sites, both in an
occupational and residential setting. Additionally, the potential
exists for exposure through consumption of contaminated ground and
surface water. Therefore, the triazines present an example where the
Agency can address pesticides with commonality of mechanism as well as
exposure through multiple pathways.
The Agency believes the triazines case study presents an
opportunity for public participation in the development of improved
risk assessment methodologies. The Agency acknowledges that there are
several ways of approaching this problem and the triazines case study
presents but one way. Moreover, the Agency welcomes input from
interested parties on this approach and sees this as an initial step in
implementing the Academy's recommendations.
A. Combining Estimated Cancer Risks Across Exposure Pathways
In the past, for the most part, the Agency has evaluated the human
health risks for various exposure pathways separately and has not
combined these risk estimates to obtain a composite risk estimate for a
single pesticide. In reality, individuals may be routinely exposed to a
given pesticide through several exposure pathways. For the triazine
herbicides, potential exposure pathways include consumption of residues
in food, consumption of contaminated drinking water, application to
agricultural commodities by both growers and commercial operators,
application around the home and post-application exposure. Rather than
quantifying exposure for every possible use, the Agency normally
focuses on the primary uses and those likely to result in the highest
exposure. This step has been performed for the triazines, with exposure
and upper bound excess individual lifetime cancer risk estimates
contained in Tables 1 through 3 and Tables 5 through 10 of this notice.
After identifying all possible exposure pathways, the next step is
to identify reasonable exposure pathway combinations that have the
potential to expose the same individual or subpopulation. For example,
drinking water may only be contaminated in a localized portion of the
country and it would be inappropriate to assume the entire population
of the United States is exposed via this pathway. It is also useful to
estimate the number of individuals potentially exposed via each
pathway. In determining whether it is reasonable to combine exposure
pathways, the temporal relationship of those exposures is relatively
unimportant as long as exposure levels are low because the multistage
model for carcinogens predicts additivity at low levels of exposure. In
other words, each additional exposure increases an individual's cancer
risk incrementally, if one is assuming a multistage model of
carcinogenesis. The possible combination of exposure pathways can be
extremely complex for pesticides with many uses, such as the triazine
herbicides. Some individuals or subpopulations will be exposed through
several pathways while others may be exposed via a single pathway
(e.g., dietary only). One approach is to develop a matrix of reasonable
exposure combinations for each triazine herbicide, with each
combination depicting exposure to a subset of the overall population.
However, as a first step, the excess individual lifetime cancer risks
should be provided for each exposure pathway and also assuming exposure
via all reasonable pathways. The remaining exposure pathway
combinations will fall within this range. In many instances, one
pathway will contribute the majority of exposure, with the other
pathways adding a negligible amount to the overall exposure and risk.
One possible combination of exposure pathways for the triazines is
outlined in the following Table 11:
Table 11.--Triazines - Upper Bound Cancer Risk Estimates Across Several
Exposure Pathways
------------------------------------------------------------------------
Exposure Pathway Atrazine Simazine Cyanazine
------------------------------------------------------------------------
Dietary.......... 4.4 x 10-5 1.1 x 10-5 2.9 x 10-5
Drinking Water\1\ 4.2 x 10-6 6.2 x 10-7 9.7 x 10-6
Occupational\2\.. 7.7 x 10-3 4.6 x 10-3 6.6 x 10-3
Residential\3\... 2.4 x 10-5 N/A N/A
------------------------------------------------------------------------
Total............ 7.8 x 10-3 4.6 x 10-3 6.6 x 10-3
------------------------------------------------------------------------
\1\ Derived from surface water.
\2\ Commercial application to corn using ground boom equipment-mixer/
loader.
\3\ Lawn treatment by homeowner using hand cyclone spreader.
Accounting for other exposure pathways, such as post-application
exposure, would increase the risk estimates for each pesticide. This
example applies to an individual who consumes contaminated drinking
water from a surface water source only, is employed as a commercial
operator, and applies an atrazine product to their lawn. The number of
individuals who are exposed via any combination of pathways likely will
be less than for each pathway by itself. The results of the analysis
indicate that one exposure pathway ``drives'' the overall risk when
combining exposure across several pathways. This result will routinely
occur when estimating cancer risks to those involved in the commercial
application of these triazine pesticides.
B. Combining Cancer Risks Across Chemicals
Individuals are routinely exposed to more than one pesticide
simultaneously in a given day, use season and/or year, either through
dietary or occupational/residential routes of exposure. For example,
individuals often apply pesticides which are tank-mixed or pre-packaged
with other active ingredients. Moreover, multiple chemical exposures
from foods may occur through consumption of a single commodity with
multiple pesticide residues and/or consumption of multiple commodities
with single or multiple pesticide residues. However, EPA risk
assessments have traditionally focussed on exposure from a single
pesticide which may underestimate risks in many instances. The Academy
highlighted this issue by recommending that EPA combine exposures of
pesticides with common mechanisms of action. The Agency's Risk
Assessment Guidelines for Chemical Mixtures, published in 1986, provide
useful guidance for assessing the overall potential for cancer and
noncancer effects posed by multiple chemicals. These guidelines can
also be applied to the case of simultaneous exposures to several
chemicals from a variety of sources and by more than one exposure
pathway. The Agency is currently in the process of revising these
guidelines.
The Agency's Risk Assessment Guidelines for Chemical Mixtures do
not recommend a single approach to assess risks from multiple chemical
exposures. Rather, the Guidelines outline a risk assessment approach
based on the quality of the toxicity database. The ideal approach for
assessing risks from chemical mixtures is to obtain toxicological data
on the mixture itself. However, as is the case with most chemical
mixtures, very little if any toxicity data are available for pesticide
mixtures. Some data are available on pesticide products containing
mixtures, but these data are usually limited to acute toxicity data and
are not useful for assessing subchronic and chronic risks or, even
acute risk, in general. Fortunately, a wealth of toxicity data is
available on single active ingredients or the various components of a
pesticide mixture. In the absence of data on the potential interaction
among the components, the Guidelines for Chemical Mixtures recommend
additive models for risk assessment of chemical mixtures. This is a
default assumption that assumes independence of action by the
pesticides involved (i.e., that there are not synergistic or
antagonistic chemical interactions and that all chemicals produce the
same effect). The Guidelines state further that ``...Based on current
information, additivity assumptions are expected to yield generally
neutral risk estimates (i.e., neither conservative nor lenient) and are
plausible for component compounds that induce similar types of effects
at the same sites of action.''
The Guidelines state that for carcinogens where linearity of the
individual carcinogenic dose-response relationships has been assumed,
it is appropriate to simply sum excess individual lifetime cancer risks
to account for exposure to several compounds. This approach assumes
independence of action and additivity among the several carcinogens.
For pesticides, summing excess cancer risks is relevant for both
product mixtures and situations where an individual may be exposed to
several pesticides, as long as exposures are small.
In the case of the triazines, a plausible argument can be made for
supporting the assumption that atrazine, simazine and cyanazine operate
through a common mechanism of action in inducing mammary tumors in the
rat. Of the currently registered triazine herbicides, these three
pesticides are all members of the 2-chloro-4,6-bis-(alkylamino)-s-
triazine subgroup. They also produce the same tumor type - malignant
mammary gland tumors in the Sprague-Dawley rat. The Agency conducted a
Structure Activity Relationship Analysis concluding that this subgroup
of triazines poses a hazard of equal concern, both qualitatively and
quantitatively, when compared with one another. The Agency has assumed
additivity and that no synergistic or antagonistic interaction between
these three chemicals exists, which is consistent with the Guidelines
on Chemical Mixtures when chemical-specific data do not exist or
contradict this assumption. Therefore, the Agency used a simple
additive approach to estimate lifetime excess cancer risks for
concurrent and sequential exposure to atrazine, simazine and cyanazine.
Each exposure pathway discussed earlier in this notice has been
addressed for atrazine, simazine and cyanazine. Additional exposure
pathways do exist (e.g., post-application exposure) which the Agency
may evaluate in the future. The dietary risk estimates for each
commodity and a total across all commodities, characterize the total
dietary risk from commodities treated with atrazine, simazine and
cyanazine as provided in Table 12:
Table 12.--Total Dietary Cancer Risk Estimates - Triazines
----------------------------------------------------------------------------------------------------------------
Commodity Atrazine Simazine Cyanazine Total
----------------------------------------------------------------------------------------------------------------
Almonds.............. 0 1.5 x 10-8 0 1.5 x 10-8
Apples............... 0 1.9 x 10-6 0 1.9 x 10-6
Avocados............. 0 2.3 x 10-8 0 2.3 x 10-8
Bananas/Plantains.... 0 5.6 x 10-8 0 5.6 x 10-8
Blueberries.......... 0 5.4 x 10-8 0 5.4 x 10-8
Caneberries.......... 0 8.6 x 10-8 0 8.6 x 10-8
Cherries............. 0 2.0 x 10-7 0 2.0 x 10-7
Corn, sweet......... 3.1 x 10-6 1.4 x 10-7 5.7 x 10-6 8.9 x 10-6
Corn, other......... 5.2 x 10-6 8.2 x 10-8 6.2 x 10-6 1.1 x 10-5
Cottonseed........... 0 0 9.3 x 10-8 9.3 x 10-8
Cranberries.......... 0 2.0 x 10-7 0 2.0 x 10-7
Currants............. 0 3.2 x 10-9 0 3.2 x 10-9
Eggs................ 1.3 x 10-6 2.1 x 10-8 1.7 x 10-6 3.0 x 10-6
Filberts............. 0 4.8 x 10-9 0 4.8 x 10-9
Grapefruit........... 0 6.2 x 10-7 0 6.2 x 10-7
Grapes............... 0 4.7 x 10-7 0 4.7 x 10-7
Guava............... 0 0 0 0
Lemons............... 0 1.2 x 10-7 0 1.2 x 10-7
Macadamia nuts....... 6.6 x 10-10 6.0 x 10-10 0 1.3 x 10-9
Milk................ 9.3 x 10-6 8.9 x 10-8 1.2 x 10-6 1.1 x 10-5
Millet............... 0 0 0 0
Olives............... 0 1.2 x 10-8 0 1.2 x 10-8
Oranges.............. 0 5.7 x 10-6 0 5.7 x 10-6
Peaches.............. 0 4.5 x 10-7 0 4.5 x 10-7
Pears............... 0 3.7 x 10-7 0 3.7 x 10-7
Pecans............... 0 5.8 x 10-9 0 5.8 x 10-9
Pineapple............ 9.0 x 10-8 0 0 9.0 x 10-8
Plums............... 0 8.9 x 10-8 0 8.9 x 10-8
Poultry meat......... 6.8 x 10-8 1.8 x 10-8 1.3 x 10-6 1.4 x 10-6
Red meat............ 2.1 x 10-6 2.8 x 10-8 1.
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