Chlorpyrifos Studies: The Debate is in the Details

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1 Chlorpyrifos Studies: The Debate is in the Details Chlorpyrifos Studies: The Debate is in the Details Page 1 of 13

2 Introduction Dow AgroSciences LLC, based in Indianapolis, Indiana, USA, is a top-tier agricultural company that combines the power of science and technology to continuously improve what is essential to human progress. Dow AgroSciences provides innovative technologies for crop protection, pest and vegetation management, seeds, traits, and agricultural biotechnology to serve the world's growing population. The safety of consumers, farmers, farm workers (applicators), and the people on manufacturing lines is not only important to us it s also mandated by law. This is why our products and pesticides in general must be submitted to rigorous testing before they ever reach the market. Chlorpyrifos long history (more than four decades of registered use) has made it one of the most thoroughly-studied pesticides on the market. It also means that there has been ample time for adverse effects to surface, especially for those in its manufacture. Yet few have been documented from authorized uses. Unfortunately, much of the negative attention chlorpyrifos has received (often perpetuated and amplified by opposition groups) has stemmed from misinformation about the product s origins, use, and acceptable exposure limits. In this paper, we analyze and clarify some of the research most frequently-cited by pesticide critics, especially those opposed to the continued use of chlorpyrifos. Chlorpyrifos is an organophosphate insecticide. Like other organophosphates, its insecticidal action is due to the inhibition of the enzyme acetylcholinesterase, resulting in the accumulation of the neurotransmitter, acetylcholine, at nerve endings. This results in excessive transmission of nerve impulses, which causes mortality in the target pest. A legitimate question is what impact chlorpyrifos has on the inhibition of these cholinesterase enzymes in the human body, and how much exposure is safe. The Basics of Cholinesterase Inhibition What Is Cholinesterase Inhibition? Cholinesterases are naturally produced by the body. In the brain or other nerve tissues, these enzymes are essential for proper nerve function. Cholinesterases become inhibited (or inactivated) when they are exposed to a variety of natural and manmade substances, including chlorpyrifos (an organophosphate) and a few other insecticides (such as carbamates). When they are inhibited in the brain or nerve tissue, normal nerve function can be compromised. Cholinesterases are also found in red blood cells and in blood plasma where they have no established function. Inhibition can occur in blood plasma and red blood cells without adverse effect, which makes blood cholinesterase an effective early warning for exposure to anticholinesterase inhibiting compounds. A Few Causes of Cholinesterase Inhibition Organophosphate insecticides (such as chlorpyrifos) Certain medications Some components of food (such as glycoalkaloinds, which are found in small amounts in potatoes) Certain health conditions (liver disease, malnutrition, anemia, hepatitis, etc.) In fact, extensive research and decades of practical experience have shown that signs and symptoms of toxicity from chlorpyrifos exposure do not occur without substantial inhibition of blood cholinesterases. 2 The EPA and other regulators have concluded that this inhibition is the most sensitive biological indicator of exposure to chlorpyrifos. Before inhibiting brain cholinesterase, chlorpyrifos exposure inhibits essentially all plasma cholinesterase and more than 30 percent of red blood cell cholinesterase, without provoking any signs or symptoms of toxicity. Thus regulatory standards, such as the EPA s, are intended to keep nonoccupational exposures to chlorpyrifos too low to inhibit blood cholinesterases and offer a wide margin of safety for human exposure by safe-guarding against the occurrence of even a nontoxic effect. 3 Chlorpyrifos Studies: The Debate is in the Details Page 2 of 13

3 For more information about how the EPA sets exposure standards, see the paper The Insecticide Chlorpyrifos: How Standards Are Set for the Protection of Human Health available on Dow AgroSciences Chlorpyrifos Protects website: Regulators Continuously Evaluate Product Safety Based on New Findings New studies are published in scientific journals every month. And when new studies appear, it is not uncommon for research proponents to report findings as novel and contrary to the entire body of scientific research previously conducted. But reaching scientific consensus about newly reported findings takes time. In order to make informed decisions about products, conclusions drawn from any particular study must be tested for accuracy and validity, evaluated in terms of what is already known, and then integrated into the total body of what is known about the product. Although new studies can be expected to prompt questions, the following can be counted on to remain true in the midst of continual change: The safety margins built into the regulation of pesticides are extensive. Current restrictions for dietary exposure have been established to provide a reasonable certainty of no harm not only for the general population but also for infants and pregnant women. These restrictions have been based on a comprehensive, transparent, and objective evaluation of extensive data. A well-defined regulatory process is already in place by which new scientific information is continuously taken into account. EPA s Exposure Limits to Chlorpyrifos (nanograms per kilogram of body weight) Non-Adverse Effect 1,000,000 No Effect 500,000 Maximum Allowable One-Time Exposure from Labeled Use 500 Maximum Allowable Daily Exposure from Labeled Use 30 Seen through the lenses of appropriate study design and execution, as well as the EPA s and Dow AgroSciences efforts to protect consumers while also providing quality food products to countries around the world, the following research studies might be examined in a different light than they are portrayed in the media. In fact, these studies underline the need to approach interpretation of their results very carefully before forming opinions about the benefits and potential risks of chlorpyrifos. New Perspectives on Controversial Chlorpyrifos Studies Scientists work diligently to make their work valid, reliable, repeatable, and credible. However, even the most carefully designed and executed study can leave itself open to interpretation. Over the years, critics opposed to the use of pesticides have used research studies as arguments to petition against their registration and use. Chlorpyrifos is no exception. However, in the more than 40 years of study associated with its manufacture and use, the collective weight of this research supports continued agricultural use of the product. While new studies and new perspectives on chlorpyrifos are actively considered by regulatory agencies, those studies must be carefully analyzed and thoroughly understood before they are presented as potential evidence of alleged danger to human and environmental health. Chlorpyrifos is one of the most thoroughly-studied pesticides on the market. Forty years of closely monitored manufacture and use and over 5,000 studies have shaped the viewpoints of both advocates for the product and its opponents. But not all research is equally relevant to the continued safety evaluations and registration of chlorpyrifos. Chlorpyrifos Studies: The Debate is in the Details Page 3 of 13

4 The following sections of this paper briefly explore a few of the arguments critics use against chlorpyrifos use and point out where and why the conclusions drawn by that research have been generally unconvincing to regulatory agencies. Duke University Injection Studies While the Duke University injection studies offer interesting insights into how targeted organs and tissue react to chlorpyrifos exposure, the prevalent feeling among most regulators and scientists is that they are not useful for risk assessment, as the outcomes are nearly impossible to interpret in real-world terms. For the past decade, researchers at Duke University have been exploring what physiological effects, other than inhibition of cholinesterase, might be caused by exposures to chlorpyrifos. Among other things, these researchers have reported that using hypodermic needles to inject chlorpyrifos at relatively high doses into the brain and body cavities of newborn rat pups affects the development of their nervous system, as well as causing other subtle effects. However, the human health significance of these studies is unclear. 5 It is important to keep these reports in perspective with the total weight of chlorpyrifos research conducted to date. Taken in context, studies by injection don t project potential risks of real-world exposure to chlorpyrifos from authorized uses, for the following reasons: Chlorpyrifos Doses Far Exceeded Valid Exposure Levels The first problem with the Duke studies concerns the strength of the doses injected into the rats. With few exceptions, the effects described by Duke University researchers have not been shown to occur in live animals except at doses at or above those needed to inhibit cholinesterase. That is, the EPA regulates chlorpyrifos to keep non-occupational exposures from authorized uses below those needed to inhibit blood cholinesterases. In this case, rats were injected with doses at 1mg/kg/BW (or 1,000,000 nanograms per kilograms of body weight) or 2,000 times above the allowable one-time maximum exposure. Of studies employing high doses such as these, members of the Society of Toxicology, the independent professional association for practicing government, industry, and academic toxicologists, have stressed: [I]t would be a step forward if more investigators keep in mind that the doses/concentrations of chemicals they are employing in laboratory experiments should bear some relationship to levels expected to be encountered in the environment. 8 Unless the effects reported by injection research can be shown to occur at doses well below those needed to inhibit cholinesterase, the findings have limited public health significance since existing regulations are already designed to keep non-occupational exposures too low for these effects to occur from authorized uses of the product. Injection Does Not Reflect Real-World Exposures Another problem with the Duke studies concerns how laboratory rats were exposed to chlorpyrifos. Current registered uses of chlorpyrifos do not authorize injection of the product into peoples bodies. People would not plausibly be exposed in this way, so conclusions drawn from exposure by injection have questionable relevance for real-world exposures. To put this in perspective: There are many common substances that people are routinely exposed to in the normal course of their lives (e.g., household bleach) that would be clearly toxic, or even lethal, if injected directly into the brain or chest cavity. If used according to directions, however, those same substances are not harmful. Chlorpyrifos exposures may occur by eating food treated with the insecticide, through the skin, and by inhalation. Therefore, guideline laboratory studies used for assessing and regulating the product have 22, 23 focused on dermal, oral, and inhalation exposures not injection. Chlorpyrifos Studies: The Debate is in the Details Page 4 of 13

5 While the most convenient way to produce adverse effects in targeted organs and tissues might be by injection, leaders in the scientific community have expressed reservations about the validity of this approach. Members of the Society of Toxicology caution: [U]se of routes of exposure and high-dose levels, set primarily for purposes of experimental convenience, should be avoided 8 Due to the inherent limitations of injection studies, regulators charged with setting exposure limits have found research of this sort largely uninterpretable and not useful for determining permissible exposures for regulatory purposes. Chlorpyrifos Doses were Mixed with a Toxic Solvent Finally, in order to inject chlorpyrifos into the bodies of rats, researchers diluted it with a solvent. Unfortunately, the particular solvent they used, dimethylsulfoxide (or DMSO), has documented toxic properties of its own. There is no agreement about how including DMSO in these injections might have affected the body s absorption and processing of the product or otherwise contributed to the outcomes described in these reports. According to the EPA, conducting an experiment by injections of chlorpyrifos mixed with DMSO makes quantitative interpretation and extrapolation of the results problematic. 7 One of the lead Duke University researchers has acknowledged that in many academic studies, the focus is more on the novelty of the findings, publication in top journals, obtaining current funding, and opening pathways to future funding than on pragmatic uses of the data collected. As a result, in many of these studies essential considerations for risk assessment such as matching methods of dosing with anticipated routes of human exposure, evaluating how the test material is taken into the body and what tissues it interacts with are deemphasized. In that sense, he added, the academic approach is entirely deficient in those attributes that are necessary components of the application of research findings to regulatory science. 9 Scientists from the Society of Toxicology concur that research of this sort can be easy to misinterpret: The relevance of experiments using doses that are many multiples of conceivable human exposures and unrealistic routes of exposure is, at most, quite dubious. Mechanisms of action may be elicited under such conditions that would not occur with relevant routes and exposure levels. To the extent that data based upon excessive doses are used for risk assessment, as has clearly happened in many cases, the predicted risks may have little or no relationship to risk in the real-world. 8 Research of this sort will surely continue. In interpreting the results of such toxicology studies for themselves, the public needs to consider three essential questions: 1. What was the dose used in the tests? 2. What was the route of exposure? 3. How does the tested dose and means of administration relate to real-world exposures? Chlorpyrifos Studies: The Debate is in the Details Page 5 of 13

6 Controversial Studies: Chlorpyrifos and Children Children s health is of undeniable importance to us all. In the past, public health standards were largely based on what was known or projected about the potential exposures to and biological responses of adults. Today, it is widely recognized that children may have exposures and responses that are unique to their behaviors and period of development. As a result, there is now a great deal of scientific research underway dedicated to identifying potential age-related differences in response to various exposures. 4 Children s health is a new and expanding field, and, as might be expected when there are many studies being published, there are many conflicting opinions about what the findings mean and how the studies all fit together. Among pesticides, chlorpyrifos receives considerable research interest, in part because there has already been a great deal of research on the product so researchers have groundwork already laid for them. Chlorpyrifos is also of ongoing interest because, as a result of its broad usage on food crops, human exposure is common. Trace levels of chlorpyrifos have been detected in human blood, and low levels of its primary metabolite, or break-down product, TCPy (trichloro-2-pyridinol) have been widely reported in human urine. (Learn more about biomonitoring: has raised concerns with some stakeholders about the use of chlorpyrifos. While some of the studies on which these concerns are based have been well-conducted, many of them pursue subtle effects into unfamiliar medical areas where proper interpretation is a significant challenge. Another challenge is posed by potentially confounding factors (e.g. study design, genetics, home environment and exposure to other substances), which often provide plausible alternate explanations for reported findings and call into question the conclusions offered by opposition groups. One of the more controversial studies comes from researchers at Columbia University that reported that exposure to chlorpyrifos prior to birth can be linked to decreased body length and weight at birth and to later childhood developmental issues. The study measured exposure to chlorpyrifos in terms of its presence in umbilical cord blood at birth. No samples were taken at gestational periods that would have 10, 11 the greatest developmental interest. These researchers also reported that the children that they classified as having had relatively high exposures to chlorpyrifos, based on a one-time measurement of umbilical cord blood at birth, had greater problems with attention and increased potential for attention deficit/ hyperactivity disorder at age three. These children also scored lower on standardized tests designed to measure psychomotor and mental development. (Read a more detailed discussion of the study s limitations: Opposition groups have used this study to fuel arguments against the use and re-registration of chlorpyrifos. At face value, the Columbia University research raises serious questions, and further research into this area will most certainly be conducted. There are compelling reasons, however, why the reported outcomes of these papers are not likely to have been caused by chlorpyrifos: Inconsistency with other similar studies Exposures reported are well below the no effect level in numerous other studies. Exposure was only estimated at one point in time. Internal evidence within the research raises concerns about the validity of the reported findings. The weight of the evidence from other studies does not support claims of risks to child development from authorized uses of chlorpyrifos. Chlorpyrifos Studies: The Debate is in the Details Page 6 of 13

7 The weight of accumulated evidence over decades of study does not support claims of chlorpyrifosrelated risk to child development. After evaluating thousands of available studies on chlorpyrifos, including those conducted by Columbia University researchers, an international panel of 13 eminent physicians, medical scientists, toxicologists and epidemiologists concluded in an extensive report published in 2008 that there is no scientific support for a cause-and-effect connection between current levels of chlorpyrifos exposure and adverse human development. 1 Access the peer-reviewed report online: Controversial Studies: Reproduction and Endocrine Function In addition to claims regarding cholinesterase inhibition and alleged potential for adverse effects on human health, a number of other claims have been made about chlorpyrifos exposure. Studies evaluating male visitors to a Massachusetts infertility clinic have reported various links between increased levels of the chlorpyrifos breakdown product TCPy and outcomes associated with reproduction, among them reduced sperm concentration and motility; and reduced testosterone levels. 15, 16, 17, 18 Before discussing the research itself, it might be helpful to provide some background on TCPy and its use as an indicator of chlorpyrifos exposure. Chlorpyrifos and TCPy Government biomonitoring studies have reported the presence of trace levels of the chlorpyrifos breakdown product TCPy (trichloro-2-pyridinol) in most samples of human urine analyzed in the United States. Chlorpyrifos critics often point to these findings as evidence that people are receiving too much exposure to chlorpyrifos. Government researchers who conduct these biomonitoring studies are generally quick to point out, however, that the detectable trace level presence of pesticides, breakdown products, or other trace contaminants in bodily fluids, such as urine, is no indication that these compounds are causing harm or that the levels found have significance for human health. 1 TCPy levels found in urine are generally accepted to have no toxicological significance. Nonetheless, TCPy has been used as an indicator of chlorpyrifos exposure. Today, it is widely accepted that chlorpyrifos, once applied to plants, readily breaks down to TCPy in the environment. In fact, the Eaton et al. review of studies points to the probability that much of the TCPy found in urine comes not as direct exposure to chlorpyrifos but from exposure to the breakdown product itself. An extensive scientific literature review authored by 13 eminent physicians, medical scientists, toxicologists, and epidemiologists published in 2008 in the peer-reviewed journal Critical Reviews in Toxicology concluded that: TCPy was an imperfect biomarker of chlorpyrifos exposure Assessing chlorpyrifos from TCPy in urine overestimated chlorpyrifos exposure 10 to 20 times (Eaton et. al, 2008) 1 No one likes the idea of pesticides or their breakdown products passing through their bodies any more than they like insect parts and insect feces in their food (though these are also unavoidably present in our diet in small amounts). While some people may find any pesticide detections of this sort disturbing, the levels noted actually provide considerable reassurance that exposures to chlorpyrifos are, in fact, within EPA s healthbased limits. Moreover, the Eaton et al. review (2008) 1 concluded that TCPy was an imperfect biomarker of chlorpyrifos exposure and that assessing chlorpyrifos from TCPy in urine overestimated chlorpyrifos exposure by ten to 20 times the actual exposure. These reviewers concluded that current exposures to Chlorpyrifos Studies: The Debate is in the Details Page 7 of 13

8 chlorpyrifos in the U.S. were less than 10 ng/kg/bw per day (which falls within health-based standards for chlorpyrifos set by the EPA). Access the peer-reviewed report online: TCPy and the Fertility Clinic Studies In addition to the fact that TCPy is, in itself, an imperfect measure of chlorpyrifos exposure, all of the TCPy levels evaluated in urine in the infertility clinic studies fell well within levels anticipated in the general population, based on extensive government biomonitoring. Studies in several animal species have shown no effect on fertility or litter size from daily doses of chlorpyrifos hundreds of times greater than any exposures that could be projected from the TCPy levels reported in these infertility clinic papers. What s more, after 40 years of manufacturing and studying chlorpyrifos, there are no reports or indications of infertility among workers involved in the production of chlorpyrifos, even though studies of these workers have shown their urinary TCPy levels to be 10 to 100 times higher than the levels reported for the men tested in this infertility clinic research. Why would these papers find effects relating to reproduction and endocrine function associated with essentially miniscule levels of TCPy in urine when no effects were noted in either animals or humans exposed to chlorpyrifos at significantly higher levels? There are several points to consider in light of these discrepancies. A fundamental weakness in these infertility clinic papers is that the researchers were only able to take biological samples from the subjects on a one-time basis, so no data were offered about TCPy levels over time. This is important because the half life of TCPy in the human body is about one day, while spermatogenesis takes about three months so the reported levels of TCPy actually provide no information about levels that existed when the sperm were being developed. Moreover, the reduced sperm concentration and motility reported in the infertility clinic research were not statistically significant for TCPy, which increases the likelihood that the association is a function of chance. The published report calls these reductions suggestive and borderline but also describes them as difficult to interpret. 18 The reported differences in testosterone levels may also be a random occurrence, since testosterone levels vary in men by as much as 30 percent based on the season and time of day and the differences in levels reported in this infertility clinic research fall within this normal variation. While the authors claim to have controlled for these variables 15, measurement of testosterone levels in blood is difficult, as endocrinologists generally acknowledge: [M]easurement of serum testosterone is still relatively unreliable and represents a significant bias when interpreting results and correlating them with biological phenomena. Unfortunately, peerreviewed journals have not contributed much to improve the reliability of published values. Therefore, all reported variations of testosterone levels and their associations with physical and mental aspects must be viewed very critically. 19 Even assuming for the moment, however, that the measurements were accurate and that the findings were not simply reflective of normal individual variation, the reported differences in testosterone levels were so small as to make their biological significance unclear. Chlorpyrifos has been extensively studied for a wide range of biological effects relating to reproduction and endocrine function. Toxicologists at regulatory agencies throughout the world have evaluated the research conducted in these areas and have not identified reproductive or endocrine issues as issues for exposures resulting from authorized uses of chlorpyrifos. Chlorpyrifos Studies: The Debate is in the Details Page 8 of 13

9 Controversial Studies: Chlorpyrifos and Cancer Chlorpyrifos critics also point to studies claiming a connection between lung cancer and chlorpyrifos exposure. However, be aware: No regulatory body in the world considers chlorpyrifos a cause of cancer. Two-year laboratory tests have been conducted in multiple species in which animals received chlorpyrifos in their feed every day of their lives at doses thousands of times greater than any anticipated exposure from authorized uses. No evidence of cancer was found in these studies. Given the magnitude of these lifetime exposures, if chlorpyrifos were a cause of cancer, these exposures would have been expected to demonstrate it. Studies of workers involved in the production of chlorpyrifos have also not shown links between chlorpyrifos exposure and cancer. Daily Chlorpyrifos Doses in Animal Studies vs. Estimated Exposures to Applicators (ng/kg/bw) High Dose in Laboratory Tests 10,000,000 (Dose given each day for a lifetime no cancer.) Anticipated Exposures to Chlorpyrifos Applicators* 2,100* * Geometric mean. Exposure estimate based on the Farm Family Exposure Study (see below), where the dose of chlorpyrifos received from application of the product was estimated based on detection of the breakdown product TCPy in urine. (The number reported is a worst-case estimate assuming that all urinary TCP derived from exposure to chlorpyrifos.) In light of this information, the claims cited by chlorpyrifos opponents bear further analysis. The Agricultural Health Study Actually a cluster of studies begun in 1993 by several federal agencies, The Agricultural Health Study looks at various factors affecting the health of farmers and farm workers. In 2004, researchers for The Agricultural Health Study reported a survey of 57,284 pesticides applicators in Iowa and North Carolina in which 50 different pesticides were evaluated as potential causes of lung cancer. 20 In essence, the researchers asked the applicators about their exposures and compared lung cancer rates among those who said that they used the products with the rates for those who said that they had not. Based on these comparisons, users of seven of the pesticides were reported to have higher rates of lung cancer than those of their peers who had not used them. Of these seven pesticides, four (chlorpyrifos, diazinon, metolachlor and pendimethalin) were reported to have increasing prevalence of lung cancer risk associated increasing estimated use of the product. Of the 57,284 applicators, there were 69 with lung cancer who reported using chlorpyrifos and 104 with lung cancer who reported never having used the product. Of these 69 applicators with lung cancer, the researchers found essentially no increased risk for lung cancer among 46 applicators who reported using chlorpyrifos less than 103 days in their lives. Of the remaining 23 applicators, some of whom reported using chlorpyrifos more than 116 days in their lives, the researchers reported a 70 percent increase in lung cancer risk. However, the findings were not statistically significant, which suggests that these results could be an outcome of chance. Other research has not confirmed the study s findings, and there are strong reasons for supposing that the risk reported in this study is attributable to factors other than chlorpyrifos. In fact, study design again raises questions. In 1998, a panel of experts formed by the Harvard Center for Risk Analysis (with an unrestricted grant from CropLife America) reviewed the study protocols for several of The Agricultural Health Study projects and cautioned that the studies in many cases: Chlorpyrifos Studies: The Debate is in the Details Page 9 of 13

10 a) lacked actual exposure data, which could lead to biased and imprecise estimates of exposure; and b) suffered from potential problems with reliability and validity as a result of the self-reporting of data on health conditions. It should be noted that the validity of findings of this study rest on how well the applicators remembered their use of the products in question, but as with any self-reporting mechanism there is reason to doubt their recollection. Previously, when Ag Health Study applicators were asked on two different occasions how many years and how many days per year they had used particular pesticides, they were only able to provide the same answer about half the time. Almost all the lung cancer cases that occurred in The Agricultural Health Study cohort were observed in current or former smokers. 22 Moreover, even if the study were, for the moment, to be taken at face value, the findings would offer no cause for concern for non-occupational exposures to chlorpyrifos, since the reported risk was found among applicators, and only among those with lifetime use of the product reported as more than 103 days. The Agricultural Health Study researchers acknowledge in their report that laboratory studies of chlorpyrifos do not demonstrate mutagenic or carcinogenic risks for chlorpyrifos and do not support claims of an association between chlorpyrifos and cancer. Of their findings, the researchers note that they cannot rule out the possibility that these are chance findings, and they caution that replication of these 20, p.885 results in other studies will be necessary before any firm conclusion can be reached. The most telling detail in the interpretation of the results appeared in a separate report from the Ag health Study focused entirely on chlorpyrifos: Of the chlorpyrifos-exposed applicators who had lung cancer, 95 percent were tobacco smokers and only four were nonsmokers. 22 In these two reports, the researchers acknowledge: Almost all the lung cancer cases that occurred in The Agricultural Health Study cohort were observed in current or former smokers. The authors caution that it was not possible to rule out residual confounding from cigarette smoking. 20 Therefore, the limitations of these studies do not justify any other conclusions than those offered by the authors themselves: namely, that the questions they raise will have to be addressed by further research. The massive amount of information being collected by the Agricultural Health Study can be expected to provide researchers with both false leads as well as true associations. Controversial Studies: Unique Enzyme-Related Susceptibility (PON1) When chlorpyrifos enters the body, it is rapidly broken down by various enzymes (e.g., carboxylesterases, cytochrome 450s and other esterases and oxonases), and then its breakdown products, such as TCPy, PON1, however, appears to be primarily a backup mechanism for detoxifying chlorpyrifos. Consequently, while animals with a less active form of PON1 have been shown to be more sensitive to relatively large doses of chlorpyrifos administered in the laboratory, PON1 type does not seem to matter with exposures consistent with authorized uses of the product. Based on extensive animal research, the EPA regulates chlorpyrifos for the protection of public health and safety by ensuring that non-occupational exposures from authorized uses are 1,000 times below the dose that caused no effect in laboratory rats. Opponents of chlorpyrifos registration have argued, however, that EPA should reduce levels of acceptable chlorpyrifos exposure even further to account for the potentially greater sensitivity of people with the less active form of PON1. Basis for the Claim In 2005, researchers at the University of Washington (Seattle) reported that genetically altered mice with a less active variant of PON1 were more sensitive to an oxidized form of chlorpyrifos than those with greater PON1 activity. 13 Based on these findings, other researchers have speculated that people with less Chlorpyrifos Studies: The Debate is in the Details Page 10 of 13

11 active PON1 variants may be more susceptible to chlorpyrifos and therefore at risk from common environmental exposures. Perspective As with most of the other studies discussed here, the doses used in the University of Washington mouse study were thousands of times greater than relevant environmental exposures. In the University of Washington study, researchers mixed chlorpyrifos with a solvent (acetone) and painted it on the shaved skins of mice, greatly magnifying the effects of this relatively massive exposure. Exposures of this magnitude cannot be legitimately compared with those that people would receive from labeled use of the product. (Nor can the potentially toxic effects of the solvent be ruled out as a contributor, as previously noted elsewhere.) Chlorpyrifos Dose Used in PON1 Laboratory Studies Compared to Nonoccupational Environmental Exposures (ng/kg/bw) Dose Used in Laboratory Study Estimated Non-occupational Environmental Exposure 3,000,000* <10** * Mixed in acetone and applied to mouse skin (Cole et al., 2005). 13 **Daily human environmental intake estimated by Eaton et al., When the doses used in the University of Washington mouse study are compared to regulatory standards and environmentally relevant exposures, it is clear that current restrictions on chlorpyrifos provide ample protection for both the population at large and for potentially sensitive individuals with less active PON1 variants. Studies of how the body breaks down chlorpyrifos have shown that that regardless of the level of PON1 activity within a given individual, PON1 is, at most, a backup or secondary means of detoxifying chlorpyrifos one that only comes into play when exposures escalate to levels high enough to overwhelm the body s primary natural defense mechanisms. At environmental exposures, however, the degree of PON1 variant activity from one person to the next has no demonstrated impact on the body s ability to neutralize chlorpyrifos. 13 Quite apart from exposure to chlorpyrifos, having less active variants of PON1 may be a genetic condition associated with developmental outcomes. In their study of newborns, for example, the Mount Sinai researchers found that children with less active PON1 variants had slightly reduced head circumferences (about a half a centimeter, or about a fifth of an inch less) regardless of whether they had significant levels of the chlorpyrifos breakdown product TCPy in their urine or not. 12 In their extensive review of research bearing on the significance of chlorpyrifos exposures to health and safety, Eaton et al. (2008), found that at low doses of chlorpyrifos, [PON1] does not appear to play a significant role in modulating chlorpyrifos metabolism, and that other detoxification pathways would be capable of compensating for the interindividual differences. Moving Forward: The Future of Chlorpyrifos Research As compelling as each of these studies seems on the surface and as significant as opposition groups have claimed them to be the issues with their design, execution, and assumptions cast significant doubt on the strength of the claims drawn from their results. Misconceptions are difficult to refute, especially when they are fueled by sensationalism and strident activism that directs attention away from scientific consensus and carefully designed, conducted, and Chlorpyrifos Studies: The Debate is in the Details Page 11 of 13

12 documented studies. While controversy can be a tool for shaping public policy, it can also interfere with objective science-based evaluations of products, such as chlorpyrifos, that provide significant benefit to national and world agriculture. Listening critically to the claims of both opponents and proponents, then carefully considering the weight of evidence in their arguments is the only way to ensure that policy best serves the public s needs. References 1. Eaton et al., Review of the Toxicology of Chlorpyrifos with an Emphasis on Human Exposure and Neurodevelopment, Critical Reviews in Toxicology, vol. 38, Supplement 2, (Cf. pp. 5, 95.) 2. Clegg et al., Determination of the Reference Dose for Chlorpyrifos: Proceedings of an Expert Panel, Journal of Toxicology and Environmental Health, Part B, 2: , Science Issue Paper: Chlorpyrifos Hazard and Dose Response Characterization, Health Effects Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, August 21, Eaton et al., Review of the Toxicology of Chlorpyrifos with an Emphasis on Human Exposure and Neurodevelopment, Critical Reviews in Toxicology, vol. 38, Supplement 2, (Cf. pp ) 5. Eaton et al., Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment, Critical Reviews in Toxicology, vol. 38, Supplement 2, (Cf. pp ) 6. Nolan et al., Chlorpyrifos: Pharmacokinetics in Human Volunteers, Toxicology and Applied Pharmacology, 73, 8-15 (1984). 7. Toxicology Chapter for Chlorpyrifos, The Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, memorandum, April 18, (Cf. p. 9.) 8. Conolly et al., Forum: Stimulating Research to Improve the Scientific Basis of Risk Assessment, Toxicological Sciences, 49, 1-4 (1999). 9. Slotkin, Theodore A., Guidelines for Developmental Neurotoxicity and Their Impact on Organophosphate Pesticides: A Personal View from an Academic Perspective, NeuroToxicology, 25 (2004) (Cf. p. 633.) 10. Whyatt et al., Prenatal Insecticide Exposures and Birth Weight and Length Among an Urban Minority Cohort, Environmental Health Perspectives, vol 112, no. 10, July 2004, pp Rauh et al., Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First Three Years of Life Among Inner-City Children, Pediatrics, vol. 118, no. 6, December 2006, pp. e1845- e Berkowitz et al., In Utero Pesticide Exposure, Maternal Paraoxonase Activity, and Head Circumference, Environmental Health Perspectives, vol. 112, no. 3, March 2004, pp Cole et al., Toxicity of Chlorpyrifos and Chlorpyrifos Oxon in a Transgenic Mouse Model of Human Paraoxonase (PON1) Q192R Polymorphism, Pharmacogenetics and Genomics, 2005, vol. 15, no. 8, pp Mattsson et al., Lack of Differential Sensitivity to Cholinesterase Inhibition in Fetuses and Neonates Compared to Dams Treated Perinatally With Chlorpyrifos, Toxicological Sciences, 2000, 53, Chlorpyrifos Studies: The Debate is in the Details Page 12 of 13

13 15. Meeker et al., The Relationship of Urinary Metabolites of Carbaryl/Napthalene and Chlorpyrifos With Human Semen Quality, Environmental Health Perspectives, 2004, 112: Meeker et al., Temporal Variability of Urinary Levels of Nonpersistent Insecticides in Adult Men, Journal of Exposure Analysis and Environmental Epidemiology, 2005, 15: Meeker et al., Exposure to Nonpersistent Insecticides and Male Reproductive Hormones, Epidemiology, 2006, 17: Meeker et al., Thyroid Hormones in Relation to Urinary Metabolites on Nonpersistent Insecticides in Men of Reproductive Age, Reproductive Toxicology, 2006, 22: Zitzmann et al., Testosterone Levels in Healthy Men and the Relation to Behavioral and Physical Characteristics: Facts and Constructs, European Journal of Endocrinology 144: , Alavanja et al., Pesticides and Lung Cancer risk in the Agricultural Health Study Cohort, American Journal of Epidemiology, 2004, 160: Perera et al., Effect of Prenatal Exposure to Airborne Polycyclic Aromatic Hydrocarbons on Neurodevelopment in the First 3 Years of Life among Inner-City Children, Environmental Health Perspectives, 2006, vol. 114, no Lee et al., Cancer Incidence among Pesticide Applicators Exposed to Chlorpyrifos in the Agricultural Health Study, Journal of the National Cancer Institute, vol. 96, no. 23, Chlorpyrifos Studies: The Debate is in the Details Page 13 of 13

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