BEFORE THE UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF PESTICIDE PROGRAMS

Office of Pesticide Programs (OPP)

Regulatory Public Docket (7502P)

Environmental Protection Agency

1200 Pennsylvania Avenue NW

Washington DC 204060

‐ 0001

Re: FIFRA Scientific Advisory Panel: Notice of Public Meeting

Docket ID: EPA

‐ HQ

‐ OPP

‐ 2009

‐ 0851

Comments on Draft Framework for Incorporating Human Epidemiologic & Incident Data in Human

Health Risk Assessment January, 7, 2010

‐ 01

‐ 21

Prepared for:

The Triazine Network

110 West 4 th Street

Garnett, Kansas 66032

Prepared by:

Gary Burin, Ph.D., MPH, DABT

gburin@tsgusa.com

Technology Sciences Group Inc.

Washington DC

February 1, 20102

The Triazine Network is respectfully submitting comments to the United States Environmental

Protection Agency’s (EPA) public docket pertaining to the Draft Framework for Incorporating Human

Epidemiologic & Incident Data in Human Health Risk Assessment.

The Triazine Network is a coalition of over 1,000 local and state agricultural associations and farmers

located throughout the United States. The coalition was established in 1995 as a result of the USEPA’s

November 1994 decision to initiate a special review of the triazine herbicides, including atrazine.

Atrazine is vitally important to the American agricultural community. Agricultural producers across the

country rely on atrazine as the foundation of their weed control programs. After more than 50 years on

the market, atrazine has become the weed control staple of American agriculture.

The members of The Triazine Network insist that the continued scientific review of atrazine use sound

science.



### Comments on January 7th EPA Framework and Case Studies

The EPA Draft “Framework for Incorporating Human Epidemiologic & Incident Data in Human Health

Risk Assessment” (“Framework”) represents, for the most part, a logical and scientifically sound

approach to the use of the growing body of nonclinical human health information for pesticides. This

Framework provides a context for the case study described in Attachment A. Based upon the approach

described in the Framework it can be concluded that the epidemiologic studies of atrazine

developmental toxicity do not add to the weight of the evidence for this herbicide.

It is recommended as per the Framework that the body of atrazine epidemiologic studies in the area of

developmental toxicity studies be examined by the SAP following the modified Bradford

‐ Hill criteria.

Individual studies and the body of evidence should be viewed in the context of consideration of dose

‐

response, temporal association, strength, consistency and specificity of association, and biological

plausibility. Following these criteria it is clear that the available studies, taken together, do not show

strong, consistent or biologically plausible effects that can be associated with atrazine exposure to

humans through drinking water and that these studies contribute little, if anything, to the weight of the

evidence for the developmental toxicity of atrazine.

The following comments pertain primarily to charge questions 1.1, 1.3, 1.4 and 2.1

‐ 4 and focus on the

utility of atrazine epidemiology studies in the Framework weight of the evidence evaluation of atrazine

developmental toxicity.

Comments on Charge Questions 1.1, 1.3 and 1.4

As noted in the EPA Framework, epidemiologic information is but one piece of the increasing vast and

diverse data base that must be considered in the US EPA Office of Pesticide Programs characterization of

the health risks of pesticides. The Framework acknowledges that epidemiologic and incident3

information should not be considered in isolation but should be viewed in the context of the extensive

array of studies, including those generated in support of pesticide registration as per the requirements

of 40 CFR Part 158 and the increasing amount of in vitro and computational information that is

becoming available.

The importance of the mode of action information is emphasized in the recent report of the National

Research Council of the National Academy of Sciences “Toxicity Testing in the 21 st Century: A Vision and

A Strategy (2007).” The evolving understanding of the role of mechanistic information, especially that

associated with the interaction of chemicals, genes and proteins, provides a basis for strengthening the

approach that has been historically used for the risk assessment of pesticides and other chemicals. As

noted by EPA, the new vision of toxicity testing and risk assessment integrates data from multiple levels

of biological organization. OPP’s approach emphasizes best available information from multiple sources

that is integrated using a weight of the evidence analysis.

Although epidemiologic studies have the potential to play an important role in human health risk

assessment, these studies often have limitations that preclude use for quantitative or even qualitative

purposes. For example, exposures to the general population, unlike those to the more highly exposed

workers, are generally inferred indirectly and through the use of surrogate information. This creates

significant uncertainty or even error regarding the association of effects with given levels of exposure to

a chemical. In addition, it is often difficult to identify and control for potential confounding factors

because populations are large and diverse. Finally, bias in study design or data collection can lead to

Type 1 or Type 2 errors (false positives or false negatives).

The EPA Framework has identified several strengths of epidemiologic information. Epidemiologic

studies may be helpful to characterize human variability if effects are observed and exposures can be

quantified. Epidemiologic studies may be used for the investigation of biological plausibility or

determination of human relevance of effects observed in laboratory animals. Null epidemiologic studies

may be used to compare to risk estimations from animal studies but population

‐ based epidemiologic

studies lacking direct measurements of exposure, such as biomonitoring or personal monitoring, usually

do not have sufficiently well

‐ characterized exposure to allow quantitative use of the study in risk

assessment. Although the document notes that high quality studies with robust exposure assessment

may be used to estimate risk quantitatively, this has rarely been possible with pesticides or other

chemicals. Calderon (2000) notes 27 cases where pollutants have been regulated by epidemiologic data

but the studies that form the basis for many of these examples are, in fact, more appropriately classified

as controlled clinical studies. Most of the pesticides in this group are regulated based upon studies in

which humans were intentionally administered known dose levels and No Observed Adverse Effect

Levels established based upon controlled dosing regimens. This is an important type of human study

that is not discussed in the Framework. It is also important to note that chemicals such as silver,

identified by Calderon (2000) as being regulated based upon epidemiologic data, have risks assessed

from human clinical data because relevant animal models for the endpoint of toxicological concern are

lacking and human data provide a more sensitive benchmark of risk than does animal models.4

Comments on Charge Questions 2.1, 2.2, 2.3 and 2.4

The Scientific Advisory Panel (SAP) has been asked by EPA to address several questions related to utility

of six specific epidemiologic studies of atrazine. The SAP has been invited to comment on the EPA

descriptions of the studies and, among other charges, to advise EPA on the integration of these studies

in the atrazine weight of the evidence analysis that is under development by the EPA.

These epidemiologic studies of adverse developmental outcomes, and the limitations of these studies,

are discussed below.

Mattix et al., (2007). Incidence of abdominal wall defects is related to surface water atrazine and nitrate

levels

. Journal of Pediatric Surgery 42:947

‐ 949.

This ecologic study compared the monthly incidences of infants born with abdominal wall defects (AWD)

in Indiana from 1995

‐ 2001 with monthly surface water atrazine levels in the Midwest determined by the

USGS. The estimated time of conception/last missed period was determined for mothers giving birth to

infants with the two studied defects, omphalocele and gastroschisis, because these defects are induced

during the fourth week of gestation 1

. Monthly comparisons of the estimated time of conception of

infants with AWD and surface water levels were reported to demonstrate a positive correlation

(p<0.0125 with Indiana State Registry data and p<0.0392 with CDC data for Indiana). The large increase

in atrazine concentrations from May to July, however, was only associated with a very small

corresponding increase in AWD in the population. More importantly, the USGS water monitoring

program does not measure atrazine (or nitrates and other pesticides) in drinking water but rather in

surface water such as rivers. Use of regional surface water data to represent potential exposure from

drinking water is not scientifically appropriate. Year

‐ to

‐ year variability of AWD in Indiana was also very

high, possibly due to the small number of Indiana infants with AWD (358 children from 1990

‐ 2001). The

incidence of AWD was seasonal but appeared to more closely track nitrate concentrations than those of

atrazine in surface water. Further, the study did not consider any other confounding factors such as

diet and is in contrast to Kristensen et al., (1997) which found no association between pesticide

exposure in farmers and the incidence of gastroschisis.

Ochoa

‐ Acuna et al. (2009). Drinking water herbicide exposure in Indiana and prevalence of small

‐ for

‐

gestational age and preterm delivery. Environ Health Perspectives 117:16191624.

This retrospective study examined whether atrazine concentrations in public water supplies in Indiana,

primarily Fort Wayne, are associated with increased incidences of preterm births or small for gestational

age (SGA) children. The potential relationship between atrazine mean and maximum water

concentrations and potential cofounders in the overall populations were assessed for preterm birth and

SGA. A total of 1,777 preterm and 3,172 preterm and SGA births out of 24,154 total births were

examined in this study. Median annual atrazine concentrations varied between municipalities. The

authors concluded that water concentrations of atrazine were associated with a significant increase in

the prevalence of SGA. The dose

‐ response, however, was not observed in the third trimester and was

1 KL Moore (1982). The Developing Human. WB Saunders Company, Philadelphia PA.5

weak when examined over the entire pregnancy. Geographic variability in the incidence of SGA was

pronounced and did not appear to correlate to atrazine water concentration. For example, localities

with low mean atrazine concentrations such as Michigan City and Stucker Fork, had the highest SGA

incidences. Although certain confounders were controlled in this study the ecological nature of this

research allows for the possibility of other environmental and social

‐ economic factors as being potential

explanations for differences in incidences. The population that was sampled was heavily weighted to Ft.

Wayne (16,393 out of 24,154 total births) and the study is therefore limited by the reliability of water

sampling in this locality and the possible confounders that may been present in Fr. Wayne but not

controlled for in the statistical analysis.

Villanueava et al., (2005). Atrazine in municipal drinking water and risk of low birth weight, preterm

delivery, and small for gestational age status. Occup Environ Med 62:400

‐ 405.

This ecologic epidemiologic study compared the incidences of low birth weight (LBW), preterm and

small for gestational weight (SGA) infants with levels of atrazine in municipal drinking water in Finistere,

Britanny, France. A total of 3510 births occurring during the period of October 1, 1997 to September

30, 1998 were analyzed in this study. The overall geometric mean atrazine level in raw and finished

water in this study was 0.071 micrograms/liter. The seasonal pattern for atrazine levels in drinking water

was not associated with increased incidences of LBW or SGA but was weakly associated with

prematurity. However, information on actual exposures to atrazine in these women was not provided.

No dose response pattern was observed with atrazine drinking water exposures and the adverse

outcomes that were examined in this study. A slightly negative dose response was observed for SGA

and atrazine levels in municipal drinking water but this relationship was not significant (p<0.066).

Winchester et al., (2009). Agrichemicals in surface water and birth defects in the United States. Acta

Paediatrica 98:664

‐ 669.

This ecological study examined monthly US birth defect rates in the period from 1996 to 2002 versus

mean monthly atrazine concentrations in surface water but not drinking water from USGS. The USGS

water monitoring program measures atrazine and other chemicals in surface waters such as rivers and

lakes but not in finished drinking water. Additionally, use of regional surface water data to represent

national exposure from drinking water is not scientifically appropriate. National raw surface water

atrazine concentrations ranged from 1.3 micrograms/liter during April

‐ July to 0.16 micrograms/liter

during other months. Birth defect rates, corrected for the time of conception as indicated by the last

missed period, peaked slightly after the peak atrazine concentration. This study had large numbers of

birth defects each month (greater than 1500) but controlled for only six potential confounders. Surface

water atrazine concentrations were reported nationally rather than locally and the analyzed water

supplies accounted for only 50% of US drinking water and reported concentrations did not reflect

concentrations in finished water. Birth defects were individually compared with raw water

concentrations and 11 of 22 types of defects were statistically significant. The birth defects that were

statistically significant showed no consistent etiology. Down syndrome, for example, is a genetic defect

induced at fertilization whereas cleft lip is induced late in gestation. Biological plausibility for the

induction of this wide variety of birth defects by a single agent is questionable. The defects that are6

statistically associated with atrazine have different in utero times of maximum susceptibility and defects

known to be linked, such as neural tube defects, are not consistently associated with atrazine exposure

in this study. Finally, seasonal variation in the incidence of specific birth defects is known but may be

due to factors other than pesticide exposure. 2

Ochoa

‐ Acuna H and C. Carbajo (2009). Risk of limb defects and mother’s home proximity to cornfilelds.

Science of the Total Environment 407:4447

‐ 4451.

This retrospective study examined the potential association of proximity to cornfields with the risk of

limb defects in children born in Indiana during the period of 2000

‐ 2004. Various potentially confounding

factors were controlled for. The population was divided in two groups consisting of those living within

500 m of greater than 3.4 ha of cornfield and those living greater within 500 m of less 3.4 ha of

cornfield. The justification for using proximity to cornfields to represent actual exposure is not provided.

The authors concluded the incidence of limb defects increased with closeness to cornfields due to a

slightly increased odds ratio for this defect. The odds ratio for this defect was only slightly increased

with proximity to soybeans. Various other factors also differ significantly with proximity to cornfields

and these include age, race, education and prenatal care. The odds ratios for other individual defects

were not significantly associated with proximity to cornfield or soy bean fields although most defects

had increased incidences with proximity to soybean fields or cornfields. Also, the authors fail to note

that farmers often rotate crops between soybeans and corn fields and pesticide exposures are therefore

mixed for populations living near corn or soybean fields. Although the proximity to cornfields does not

necessarily mean that individuals are exposed to atrazine or involved with farm activity, one

interpretation of the study results is as confirmation of previous studies showing that infants of mothers

involved with farm activities are more likely to have birth defects regardless of pesticide exposure

history 3

.

Weight of the Evidence Considerations

Epidemiology studies of pesticides should not be viewed in isolation. Atrazine has been subjected to a

thorough review by the EPA which followed the stringent standards imposed by the Food Quality

Protection Act as a requirement for reregistration. Pesticides, especially food use pesticides, are among

the best studied and most thoroughly evaluated substances to which humans are exposed. Atrazine, for

example, has been the subject of over 6000 published studies and almost 7000 studies conducted for

regulatory authorities by the primary registrant. The atrazine database includes over 50 mode of action

(MOA) studies, six developmental toxicity and four reproduction studies. These studies provide a firm

foundation for the assessment of atrazine human health risks. This large body of health and safety data

available for atrazine will be reviewed in detail during the course of April 2010 SAP meeting.

2 See Elwood JM (1975). Seasonal variation in anencephalus in Canada. Br J Prev Soc Med 29(1):22

‐ 26.

3 Pierik et al., (204). Maternal and paternal factors for hypospadia and cyptochordism: a case control study in

newborn boys. Environ Health Perspect 112:1570

‐ 1576.