Organophosphates and Outdoor Air Concentrations

Organophosphates and Outdoor Air Concentrations

Referencing: Correlating Agricultural Use of Organophosphates with Outdoor Air Concentrations: A Particular Concern for Children

Harnly et al. (2005) suggested that measured air concentrations of organophosphate insecticides may pose a particular concern for children's health. However, when considering the current scientific weight of evidence, their conclusions cannot be supported for two reasons: first, they did not demonstrate a particular concern for children based on their results, and second, they cited incomplete and inappropriate literature to support the notion that recent toxicologic and epidemiologic studies indicate a health concern.

Harnly et al. (2005) did not conduct a risk assessment to demonstrate a concern for children. Rather, they detected pesticides in air concentrations in agricultural areas and then suggested there may be a concern for children because of recent toxicologic and epidemiologic studies. Their observed median exposures of all three active ingredients (chlorpyrifos, diazinon, and malathion) were all low and well within established regulatory limits. A risk assessment approach would have been quite useful. For chlorpyrifos, Harnly et al. (2005) detected a 20-day median concentration in air of 0.000033 mg/m³. A tier-1 risk assessment assuming an air concentration of chlorpyrifos at 0.000033 mg/m³, the mean body weight of a 1- to 2-year-old child of 12.3 kg, a child inhalation rate of 6.8 m³/day, and 24-hr outdoor respiration results in a chlorpyrifos inhalation exposure of 0.0000182 mg/kg/day. Margins of exposure (MOE) would be 5,495 [acute inhalation no observed adverse effect level (NOAEL) = 0.1 mg/kg/day], 27,473 (acute NOAEL = 0.5 mg/kg/day), and 1,648 (chronic NOAEL = 0.03 mg/kg/day). All MOEs are greater than the U.S. Environmental Protection Agency (EPA) target MOE of 1,000 for infants, children, and females 13-50 years of age (U.S. EPA 2002).

More problematic is that Harnly et al. (2005) stated that

Recent cellular, animal, and human evidence of toxicity, particularly in newborns, supports the public health concern indicated by initial risk estimates.

The authors did not provide a sufficiently thorough review of the literature relevant to risk assessment to support or refute their statement. In the case of chlorpyrifos, this statement cannot be supported by the available evidence. The principal problem with Harnly et al.'s approach is not unique to their article. Appropriate risk assessment requires appropriate data, and, as simple as this relationship sounds, it is often ignored. Harnly et al. (2005) cited toxicity and epidemiologic studies, but these particular studies are not appropriate for use in risk assessment. This problem has become so pervasive that Conolly et al. (1999) clarified the basic features of toxicology studies that are and are not appropriate for use in risk assessment.

Harnly et al. (2005) should not have included the findings of Qiao et al. (2002) because the high doses, subcutaneous route of administration, and carrier were inappropriate for toxicologic risk assessment (Conolly et al. 1999; Zhao et al. 2005). Indeed, Slotkin (2004), a coauthor of Qiao, has written that there is little academic interest in relevant routes of exposure or pharmacokinetics. He stated that

Practical issues that are critical to standardized testing are de-emphasized, such as pharmacokinetics/toxicokinetics, the matching of routes of exposure to those of humans in industrial, agricultural or domestic settings, or the development of biologically-based dose response models of established hazards. In that sense, the academic approach is entirely deficient in those attributes that are necessary components of the application of research findings to regulatory science.

Harnly et al. (2005) cited Eskenazi et al. (1999) as a source of concern for adverse consequences of organophosphate exposure. To be complete, Eskenazi et al. (2004) provide more information. They stated, "We failed to demonstrate an adverse relationship between fetal growth and any measure of in utero organophosphate pesticide exposure." An association was found for a couple of variables and decreased gestational duration, but the conclusion was that these potential pesticide effects appear to have "little clinical impact at the population level."

Finally, air concentrations have been shown to translate poorly into systemic exposure. Hore et al. (2005) showed that children in houses treated with chlorpyrifos had no detectable increase in urinary 3,5,6-trichloropyridinol (TCP), whereas median peak ambient air chlorpyrifos increased > 10-fold (median of 14 ng/m³ pretreatment, 196 ng/m³ on day of treatment). If a 10-fold increase in air chlorpyrifos does not cause a detectable increase in urinary TCP, then the 1-fold background air cannot be contributing measurably to the children's background levels of urinary TCP.

The author was employed by Dow AgroSciences, a registrant of chlorpyrifos, from 1995 through 2001. Since he has been at Montana State University, he has received two unrestricted grants from Dow AgroSciences or The Dow Chemical Company to support his environmental risk assessment research. Additionally, he has had one research contract with Dow AgroSciences. None of the fundings has involved research or other activities on chlorpyrifos.

Robert K. D. Peterson
Agricultural and Biological Risk Assessment
Department of Land Resources and Environmental Sciences
Montana State University
Bozeman, Montana
E-mail: bpeterson@montana.edu

References

Conolly RB, Beck BD, Goodman JI. 1999. Stimulating research to improve the scientific basis of risk assessment. Toxicol Sci 49:1-4.

Eskenazi B, Bradman A, Castorina R. 1999. Exposures of children to organophosphate pesticides and their potential health effects. Environ Health Perspect 107(suppl 3):409-419.

Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, et al. 2004. Association of in utero organophosphate pesticide exposure and fetal growth and length of gestation in an agricultural population. Environ Health Perspect 112:1116-1124. [CrossRef].

Harnly M, McLaughlin R, Bradman A, Anderson M, Gunier R. 2005. Correlating agricultural use of organophosphates with outdoor air concentrations: a particular concern for children. Environ Health Perspect 113:1184-1189.

Hore P, Robson M, Freeman N, Zhang J, Wartenberg D, Ozkaynak H, et al. 2005. Chlorpyrifos accumulation patterns for child-accessible surfaces and objects and urinary metabolite excretion by children for 2 weeks after crack-and-crevice application. Environ Health Perspect 113:211-219.

Qiao D, Seidler FJ, Padilla S, Slotkin TA. 2002. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period? Environ Health Perspect 110:1097-1103.

Slotkin TA. 2004. Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective. Neurotoxicology 25(4):631-640. [CrossRef].

U.S. EPA. . 2002. Interim Reregistration Eligibility Decision for Chlopyrifos. EPA 738-R-01-007. Washington, DC: U.S. Environmental Protection Agency.

Zhao Q, Gadagbui B, Douson M. 2005. Lower birth weight as a critical effect of chlorpyrifos: a comparison of human and animal data. Regul Toxicol Pharm 42:55-63.

Organophosphates and Outdoor Air: Harnly et al. Respond

Peterson is incorrect in stating that we did not conduct a risk assessment. We summarized in our article (Harnly et al. 2005) and detailed in a previous article (Lee et al. 2002) a human health risk assessment demonstrating elevated acute and subchronic risks for children's exposures to ambient chlorpyrifos air concentrations in agricultural communities. Compared with the assessment by Peterson, we used a more refined probability distribution analysis, included air levels of the degradation product (chlorpyrifos oxon), and presented exposures relative to reference values. The chlorpyrifos reference values, however, were based on the same no-observed-adverse-effect levels (NOAELs) and the same 10-fold intraspecies and interspecies, and child uncertainty factors used in Peterson's calculations.

In our article (Harnly et al. 2005), we suggested that our risk assessment may underestimate risks for several reasons, such as a) risk assessments that use NOAELs, and not the entire dose-response curve, tend to underestimate risks (Castorina and Woodruff, 2003); and b) the true ranges of intraspecies and interspecies variability are unknown and may be larger than the factors used (Eskenazi et al. 1999; Faustmann et al. 2000). In a very recent study, some newborns were 65-130 times less able to metabolize diazoxon and chlorpyrifos oxon than their mothers (Furlong et al. 2006). To further support the concern for children indicated by our quantitative risk assessment, we cited toxicologic studies establishing that in addition to chloinesterase inhibition, on which the NOAEL for chlorpyrifos is established, chlorpyrifos and chlorpyrifos oxon have other neurodevelopmental toxicity mechanisms (Huff et al. 1994; Qiao et al. 2002). We also noted that cell death has been induced at the reference dose for drinking water (Greenlee et al. 2005).

Peterson argues that the toxicologic studies we cited (Castorina and Woodruff, 2003; Eskenazi et al. 1999; Faustmann et al. 2000; Greenlee et al. 2005; Huff et al. 1994; Qiao et al. 2002) are an insufficient review of the "literature relevant to risk assessment" and that these studies are not appropriate for use in risk assessment. However, in missing the fact that we conducted a quantitative risk assessment, Peterson is misinterpreting our citations as the only basis for our public health concern. We consider it our public health responsibility to, at least qualitatively, consider recent toxicologic data in addition to a quantitative risk assessment based on established reference values. Others have argued for a complete restructuring of risk assessment for children, including toxicokinetic modeling and assessment of cellular and molecular outcomes over the entire lifespan of experimental subjects (Landrigan et al. 2004).

For many reasons we disagree with the suggestion that the epidemiologic fetal growth and gestational duration findings of Eskenazi et al. (2004) may be used to disregard concern for in utero and child organophosphate exposure highlighted by Eskenazi et al. (1999). The associations of reduced gestational duration with dimethyl organophosphate urinary metabolites and chloinesterase inhibition were not clinically significant in the California population studied (recent Mexican immigrants who tend to have very healthy birth outcomes). However, a shortened gestational age of a half-week would represent, for some women, a risk of preterm delivery (Eskenazi et al. 2004). Clearly, this finding and the absence of any adverse association between fetal growth and measures of in utero pesticide exposure need to be confirmed or refuted. To be complete, however, we also cited the association found in a New York City population between low birth weight and length and cord plasma levels of chlorpyrifos and diazinon (n = 314) (Whyatt et al. 2004). Further, effects of organophosphate pesticide exposure on early child neurodevelopment have been found (Young et al. 2005) and are continuing to be evaluated in the California and the New York City cohorts. Finally, public health policy is typically developed to protect against a 1 in 1,000, or lower, risk, and the epidemiologic studies cited here are below the sample size necessary to detect such risks.

Peterson notes that a study of children in 10 homes did not demonstrate an association with child urine metabolite levels of chlorpyrifos and ambient air levels following crack and crevice treatment (Hore et al. 2005). Yet, the authors of that study were careful to note a number of study limitations, including the variability and accuracy of the child urinary metabolite readings. We also note that chloryprifos oxon, which also breaks down into the measured urinary metabolite, was not measured in air; air concentrations in four of the study homes were not elevated compared to pretreatment levels; and personal air samples were not collected (Hore et al. 2005). Among mothers in New York City (n = 314) in another study, 48-hr personal air samples collected during pregnancy were associated with cord and maternal blood levels of chlorpyrifos (Whyatt et al. 2004). This is the same study population within which an association with adverse birth outcomes and pesticide cord blood levels has been demonstrated, and the chlorpyrifos air levels are in the same (average, 15 ng/m³) range, if not lower, as those evaluated in our health risk assessment (Whyatt et al. 2004).

The authors declare they have no competing financial interests

Martha Harnly
Robert McLaughlin
Robert Gunier
California Department of Health Services
Richmond, California
E-mail: mharnly@dhs.ca.go

Asa Bradman
University of California
Berkeley, CA

Meredith Anderson
Impact Assessment Inc.
Richmond , CA

References

Castorina R, Woodruff TJ. 2003. Assessment of potential risk levels associated with U.S. Environmental Protection Agency reference values. Environ Health Perspect 111:1318-1325. [CrossRef].

Eskenazi B, Bradman A, Castorina R. 1999. Exposures of children to organophosphate pesticides and their potential health effects. Environ Health Perspect 107(suppl 3):409-419.

Faustman EM, Silbernagel SM, Fenske RA, Burbacher TM, Ponce RA. 2000. Mechanisms underlying children’s susceptibility to environmental toxicants. Environ Health Perspect 108(suppl 1):13-21.

Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B. 2006. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenet Genomics 16(3):183-190.

Greenlee AR, Ellis TM, Berg RL. 2004. Low-dose agrochemicals and lawn-care pesticides induce developmental toxicity in murine preimplantation embryos. Environ Health Perspect 112:703-709.

Huff RA, Corcoran JJ, Anderson JK, Abou-Donia MB. 1994. Chlorpyrifos oxon binds directly to muscarinic receptors and inhibits cAMP accumulation in rat striatum. J Pharmacol Exp Ther 269:329-335.

Landrigan PJ, Kimmel CA, Correa A, Eskenazi B. 2004. Children’s health and the environment: public health issues and challenges for risk assessment. Environ Health Perspect 112:257-265. [CrossRef].

Lee S, McLaughlin R, Harnly M, Gunier R, Kreutzer R. 2002. Community exposures to airborne agricultural pesticides in California: ranking of inhalation risks. Environ Health Perspect 110:1175-1184.

Qiao D, Seidler FJ, Padilla S, Slotkin TA. 2002. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period? Environ Health Perspect 110:1097-1103.

Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. 2004. Prenatal insecticide exposures and birth weight and length among an urban minority cohort. Environ Health Perspect 112:1125-1132.

Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, et al. 2005. Association between in utero organophosphate pesticide exposure and abnormal reflexes in neonates. Neurotoxicology 26(2):199-209.

Last Updated: June 22, 2006