A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the insecticide dimethoate.

1. Dimethoate is an organophosphate insecticide that is converted in vivo to omethoate, the active toxic moiety. Omethoate inhibits acetylcholinesterase (AChE) in the brain and red blood cells (RBCs). This paper describes the development of rat and human physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models for dimethoate.2. The model simulates the absorption and distribution of dimethoate and omethoate, the conversion of dimethoate to omethoate and to other metabolites, the metabolism and excretion of omethoate, and the inhibition of RBC and brain AChE. An extensive data collection program to estimate metabolism and inhibition parameters is described.3. The suite of models includes an adult rat, post-natal rat, and human model. The rat models were evaluated by comparing model predictions of dimethoate and omethoate to measured blood time course data, and with RBC and brain AChE inhibition estimates from an extensive database of in vivo AChE measurements.4. After the demonstration of adequately fitted rat models that were robust to sensitivity analysis, the human model was applied for estimation of points-of-departure (PODs) for risk assessment using the human-specific parameters in the human PBPK/PD model. Thus, the standard interspecies uncertainty factor can be reduced from 10X to 1X.

Conversations about the Future of Dicamba: The Science Behind Off-Target Movement.

Dicamba is an important herbicide for controlling post-emergent resistant weeds in soybean farming. Recently, the scientific community and general public have further examined off-target transport mechanisms (e.g., spray drift, volatilization, and tank contamination) and the visual responses of soybeans to ultralow dicamba concentrations. This paper synthesizes key chemical concepts and environmental processes associated with dicamba formulations, transport mechanisms, drift measurements, and plant responses. This paper proposes additional areas of research and actions to increase our understanding and communicate the science findings, which should provide farmers with more robust tools and practices for sustainable dicamba use.

Inhibition Kinetics of 16 Organophosphorus Pesticides or Their Active Metabolites on Erythrocyte Acetylcholinesterase From Humans and Rats.

Inhibition kinetics assays were conducted with 16 commercial organophosphate (OP) pesticides or their metabolites on acetylcholinesterase (AChE) in erythrocyte "ghost" preparations from 18 individual humans (both sexes; adults, juveniles, and cord blood samples; mixed races/ethnicities) and pooled samples from adult rats (both sexes). A well-established spectrophotometric assay using acetylthiocholine as substrate and a chromogen was employed. The kinetic parameters bimolecular rate constant (ki), dissociation constant (KI), and phosphorylation constant (kp) were calculated for each compound. As expected, a wide range of potencies were displayed among the tested compounds. Statistical analysis of the resultant data indicated no differences in sex, age, or race/ethnicity among the human samples that are unexpected based on chance (4.2% statistically significant out of 48 parameters calculated) and no differences between the sexes in rats. The bimolecular rate constants for 10 of the compounds were not statistically different between rats and humans. The data indicate that, consistent with the high level of conservation of AChE among species and the fact that AChE at different locations within a species arises from the same gene, the inhibition kinetic parameters calculated from rat erythrocyte ghost preparations should be useful in estimating potencies of OP compounds on target AChE in humans. Additionally, the data indicate that differences in sensitivities among individual humans were not apparent.

Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

The purpose of the present investigation is to analyze the in vivo genotoxicity dose-response data of ethylene oxide (EO) and the applicability of the derived point-of-departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chromosomal damage in various tissues were considered the most relevant for assessing risk from EO, since these effects are likely to contribute to adverse health consequences in exposed individuals. The PoD estimates were screened for precision and the values were divided by data-derived adjustment factors. For gene mutations, the lowest PDE was 285 parts per trillion (ppt) based on the induction of lacI mutations in the testes of mice following 48 weeks of exposure to EO. The corresponding lowest PDE value for chromosomal mutations was 1,175 ppt for heritable translocations in mice following 8.5 weeks of EO exposure. The lowest PDE for chromosomal aberrations was 238 ppt in the mouse peripheral blood lymphocytes following 48 weeks of inhalation exposure. The diverse dose-response data for EO-induced genotoxicity enabled the derivation of PoDs for various endpoints, tissues, and species and identified 238 ppt as the lowest PDE in this retrospective analysis.

CLARITY-BPA Core Study: Analysis for non-monotonic dose-responses and biological relevance.

The results of a large 2-year bisphenol A (BPA) rat study conducted by the NTP, called the CLARITY-BPA Core Study, were recently released. This study addressed some of the toxicological issues associated with BPA, including endocrine disruption and non-monotonic dose responses (NMDR). The study involved oral gavage treatment of rats to BPA at doses of 2.5-25,000 µg/kg-bw/day. To address NMDR, the 81 statistically significant findings (based on the primary statistical tests) from the Core Study were evaluated using a recently published methodology that relies upon six checkpoints to determine if there is evidence for a NMDR. Failure to meet the majority of the checkpoints indicates limited evidence of NMDR. The analysis found that only 2 of the 81 findings met at least 5 of the checkpoints: an increase in percent basophils in stop-dose females and decreased total bile acids in stop-dose males. However, these findings are not concordant or consistent with those of other BPA data. Importantly, none of the endocrine-related or reproductive endpoints fulfilled at least 5 of the checkpoints. This analysis found limited evidence for NMDR associated with BPA treatment in the study. These results are consistent with the conclusions reached in the Core Study report.

A review of epidemiologic studies of low-level exposures to organophosphorus insecticides in non-occupational populations.

This paper systematically reviews epidemiologic studies related to low-level non-occupational exposures to organophosphorus (OP) insecticides. Many of the studies evaluate levels of maternal OP metabolites and subsequent health outcomes in offspring. The studies focused primarily on birth outcomes (e.g., infant body weight or head circumference) and neurodevelopmental (e.g., mental and psychomotor) testing results. The evidence from these studies was reviewed under the Bradford Hill guidelines. Most of the studies assessing exposure based on urinary levels of OP insecticide metabolites used only one or two measurements during pregnancy. The potential for exposure misclassification with this method is largely due to (1) preformed metabolites that are ingested with food, (2) the short elimination half-life of OP insecticides, and (3) lack of specificity to particular OP insecticides for many of the metabolites. For birth outcomes, the majority of reported results are not statistically significant, and the associations are inconsistent within and across studies. There is more within-study consistency for some of the neurodevelopmental testing results, although few associations were examined across several studies. These associations are generally weak, have been replicated only to a limited extent, and require further confirmation before they can be considered established. The OP insecticide levels measured in the epidemiologic studies are too low to cause biologically meaningful acetylcholinesterase inhibition, the most widely used metric for OP insecticide toxicity. Overall, the available evidence does not establish that low-level exposures to OP insecticides cause adverse birth outcomes or neurodevelopmental problems in humans.

Associations of consumption of fruits and vegetables during pregnancy with infant birth weight or small for gestational age births: a systematic review of the literature.

Maternal nutrition is recognized as one of the determinants of fetal growth. Consumption of fruits and vegetables is promoted as part of a healthful diet; however, intakes are typically lower than recommended levels. The purpose of this study was to systematically review results from studies examining the relationship between maternal consumption of fruits and vegetables during pregnancy with infant birth weight or risk for delivering a small for gestational age baby. A comprehensive search of PubMed and EMBASE was conducted and abstracts were screened using predefined criteria. Eleven relevant studies were identified and systematically reviewed, including six prospective cohort studies, three retrospective cohort studies, and two case-control studies. Seven studies were conducted in cohorts from highly developed countries. One prospective study from a highly developed area reported increased risk for small for gestational age birth by women with low vegetable intakes (odds ratio 3.1; 95% confidence interval 1.4-6.9; P=0.01); another large prospective study reported a 10.4 g increase in birth weight per quintile increase in fruit intake (95% confidence interval 6.9-3.9; P<0.0001) and increases of 8.4 or 7.7 g per quintile intake of fruits and vegetables (combined) or fruits, vegetables, and juice (combined), respectively. One retrospective study reported an association between low fruit intake and birth weight. In less developed countries, increased vegetable or fruit intake was associated with increased birth weight in two prospective studies. Overall, limited inconclusive evidence of a protective effect of increased consumption of vegetables and risk for small for gestational age birth, and increased consumption of fruits and vegetables and increased birth weight among women from highly developed countries was identified. Among women in less developed countries, limited inconclusive evidence suggests that increased consumption of vegetables or fruits may be associated with higher infant birth weight. The available evidence supports maternal consumption of a variety of fruits and vegetables as part of a balanced diet throughout pregnancy.

Estimation of cancer risks and benefits associated with a potential increased consumption of fruits and vegetables.

The current paper provides an analysis of the potential number of cancer cases that might be prevented if half the U.S. population increased its fruit and vegetable consumption by one serving each per day. This number is contrasted with an upper-bound estimate of concomitant cancer cases that might be theoretically attributed to the intake of pesticide residues arising from the same additional fruit and vegetable consumption. The cancer prevention estimates were derived using a published meta-analysis of nutritional epidemiology studies. The cancer risks were estimated using U.S. Environmental Protection Agency (EPA) methods, cancer potency estimates from rodent bioassays, and pesticide residue sampling data from the U.S. Department of Agriculture (USDA). The resulting estimates are that approximately 20,000 cancer cases per year could be prevented by increasing fruit and vegetable consumption, while up to 10 cancer cases per year could be caused by the added pesticide consumption. These estimates have significant uncertainties (e.g., potential residual confounding in the fruit and vegetable epidemiologic studies and reliance on rodent bioassays for cancer risk). However, the overwhelming difference between benefit and risk estimates provides confidence that consumers should not be concerned about cancer risks from consuming conventionally-grown fruits and vegetables.

Acetylcholinesterase inhibition dose-response modeling for chlorpyrifos and chlorpyrifos-oxon.

This paper evaluates new data for cholinesterase inhibition with chlorpyrifos (CPF). Marty et al. (2012) recently conducted a CPF cholinesterase inhibition study in rats that included testing of males and females, dosing by gavage or diet, administration in corn oil or milk, and with pups and adults. Additionally, the study included cholinesterase inhibition testing for CPF-oxon, the active moiety that inhibits cholinesterase. The study included 5-6 dose groups with eight animals/sex/group for most of the tests. This paper provides a benchmark dose (BMD) analysis of the data from Marty et al. (2012), including a BMD meta-analysis that includes CPF cholinesterase inhibition data from different assays within the Marty et al. (2012) study and, in one case, from another study. From the meta-analysis, the recommended BMD(10)s, based on brain acetylcholinesterase inhibition, are 1.7 mg/kg/day (BMDL10 = 1.3mg/kg/day) for acute doses to children and adults, and 0.67 mg/kg/day (BMDL10 = 0.53 mg/kg/day) for repeat doses to children and adults. At the dose levels considered in this analysis, there was no evidence of a difference in responses between males and females, corn oil versus milk administration, or pups versus adults. The data on pups versus adults show that an extra safety factor to protect the young is not needed for CPF. CPF data from the literature suggest that brain cholinesterase inhibition is the most appropriate metric for cholinesterase inhibition risk assessment.

Generalized Haber's law for exponential concentration decline, with application to riparian-aquatic pesticide ecotoxicity.

A simple analytic solution to the dynamic version of Haber's law was derived, conditional on a specified toxic load exponent (n) and on exponential decline in environmental toxicant concentration. Such conditions are particularly relevant to assessing ecotoxicity risk posed (e.g., to juvenile salmonids) by agricultural organophosphate (OP) pesticides that are subject to degradation and/or dissipation. A dynamic Haber's law model was fit to previously published detailed data on lethality for two aquatic species induced by six agricultural OP pesticides, and more crude fits were obtained to less detailed data on five other OP and on two non-OP pesticides, indicating that for lethality, a range of 0.5 ≤ n ≤ 1.5 may be typical for OP pesticides. The AgDRIFT(®) stream deposition model was next used to establish that first-order or exponential loss, with dilution half-times on the order of ≤0.01 days, pertains approximately to pesticide residues in streams that arise after aerial application of agricultural pesticides 100 feet upwind. The analytic model was then applied to demonstrate that pesticide concentrations deposited in downwind streams following an aerial application are effectively diluted by about 50- to 300-fold from their initial concentration. Riparian ecotoxicity risk assessment models that ignore this effective dilution, and base pesticide-specific estimates of reduced survival on the initial concentrations, are therefore unrealistically conservative.

An ecological risk assessment for triclosan in the terrestrial environment.

Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) is a broad-spectrum bactericide used throughout North America and Europe for a variety of antimicrobial functions. This paper addresses the risk to terrestrial organisms from several potential exposure pathways: Exposure experienced by earthworms, terrestrial plants, and soil microorganisms as the result of the use of sewage sludge containing triclosan as an agricultural soil amendment; secondary exposure by birds and mammals from consumption of earthworms that have been exposed to triclosan in soil; and secondary exposure by birds and mammals from consumption of fish exposed to triclosan as the result of wastewater treatment discharges. The assessment found satisfactory margins of safety for plants, earthworms, birds, fish, mammals, and soil microorganisms. The lowest margins of safety were for nontarget plants (100 for the typical scenario and 8 for the upper-bound scenario). However, these margins of safety are still above the European Union (EU) recommended fivefold assessment value for nontarget plants and are based on cucumber results from a vegetative vigor study conducted in quartz sand that is of limited relevance for risk assessment. In a pre-emergence study conducted in a more relevant soil (sandy loam), cucumbers showed no response to triclosan at the highest dose tested (1,000 microg/kg). A recent study provides limited field measurements of soil and earthworm concentrations. While that study finds higher soil and earthworm concentrations than were estimated in the present study, even these higher concentrations do not indicate significant risks.

Evidence of health impacts of sulfate-and nitrate-containing particles in ambient air.

Ambient particulate matter (PM) is a complex mixture of inorganic and organic compounds. The U.S. Environmental Protection Agency (EPA) regulates PM as a criteria pollutant and promulgates National Ambient Air Quality Standards for it. The PM indicator is based on mass concentration, unspecified as to chemical composition, for specific size fractions. The numerical standards are based on epidemiologic evidence of associations between the various size-related particle mass concentrations as indicators and excess mortality and cardiorespiratory health effects as endpoints. The U.S. National Research Council has stated that more research is needed to differentiate the apparent health effects associated with different particle chemical constituents. Sulfate and nitrate constitute a significant portion of the particle mass in the atmosphere, but are accompanied by similar amounts of carbonaceous material, along with low concentrations of various species, including bioactive organic compounds and redox cycling metals. Extensive animal and human toxicology data show no significant effects for particles consisting only of sulfate and nitrate compounds at levels in excess of ambient air concentrations. A few epidemiologic studies, including both short-term time-series studies and long-term cohort studies, have included the sulfate content of PM as a specific variable in health effect analyses. There are much less data for nitrate. The results from the epidemiologic studies with PM sulfate are inconsistent. A detailed analysis of the time-series epidemiological studies shows that PM sulfate has a weaker "risk factor" than PM2.5 for health effects. Since sulfate is correlated with PM2.5, this result is inconsistent with sulfate having a strong health influence. However, there are many limitations with these types of studies that warrant caution for any comparison between a chemical component and mass concentration. In total, the epidemiologic and toxicologic evidence provide little or no support for a causal association of PM sulfate and health risk at ambient concentrations. For nitrate-containing PM, virtually no epidemiological data exist. Limited toxicological evidence does not support a causal association between particulate nitrate compounds and excess health risks. There are some possible indirect processes through which sulfate and nitrate in PM may affect health-related endpoints, including interactions with certain metal species and a linkage with production of secondary organic matter. There is insufficient evidence to include or exclude these processes as being potentially important to PM-associated health risk.

Use of benchmark dose and meta-analysis to determine the most sensitive endpoint for risk assessment for dimethoate.

A meta-analysis of several rat toxicity studies for dimethoate was conducted to determine the most sensitive endpoint for use in risk assessment. The analysis was motivated by a recent developmental neurotoxicity (DNT) study, which identified the same no observed adverse effect level (NOAEL) for pup mortality and cholinesterase inhibition. The pup mortality NOAEL was lower than that determined in a range-finding study for the DNT and other reproduction studies, and was highly influenced by a single total litter loss in the middle dose group, which made interpretation difficult. First, a meta-analysis was conducted of four recent studies by gavage dosing with very similar designs, including the DNT. Benchmark dose (BMD) modeling was used to determine the appropriate point of departure for regulatory purposes, the lower limit of the BMD for a 5% incidence for pup mortality (BMDL(5)) and the lower limit of a 10% inhibition of brain cholinesterase (BMDL(10)*), the asterisk denotes that the BMD is based on continuous response variable as opposed to an incidence level. For pup mortality, the BMDL(5) for post-natal days (PND) 1-4 was 0.64 mg/kg/day. For cholinesterase inhibition, the lowest BMDL(10)* was 0.19 mg/kg/day for the dams at gestation day 20. These results show that the regulatory point-of-departure for cholinesterase inhibition is more than threefold lower than pup mortality. Thus, risk assessments protecting against cholinesterase inhibition are likely to also be protective of pup mortality. In addition, cholinesterase inhibition and pup mortality were evaluated in two 2-generation reproduction studies by dietary exposure. Also, cholinesterase inhibition was evaluated in a 28-day dietary study. Dietary exposure is more relevant than gavage exposures for many human risk assessment scenarios. There was no consistent pup mortality at the highest doses of the two 2-generation dietary studies (6.0 and 6.5mg/kg/day). The average BMD(10)s for brain cholinesterase inhibition for the 2-generation studies was 0.65 mg/kg/day, with a range of 0.49--0.96 mg/kg/day. This suggests that cholinesterase inhibition is at least a 10-fold more sensitive endpoint than pup mortality for dietary exposures. For the 28-day dietary study, the BMD(10) for brain cholinesterase inhibition was 1.1mg/kg/day for males and 0.70 mg/kg/day for females. The exposure duration in the 28-day dietary study is closest to the durations in the gavage studies. Compared to the dams in the gavage studies, which had a BMDL(10) of 0.19 mg/kg/day, the animals were more than threefold more sensitive to cholinesterase inhibition by gavage compared to dietary exposure.

A framework and case study for exposure assessment in the Voluntary Children's Chemical Evaluation Program.

A conceptual framework is presented for conducting exposure assessments under the U.S. EPA's Voluntary Children's Chemical Evaluation Program (VCCEP). The VCCEP is a voluntary program whereby companies that manufacture chemicals of potential concern are asked to conduct hazard, exposure, and risk assessments for the chemicals. The VCCEP is unique in its risk-based, tiered approach, and because it focuses on children and requires a comprehensive consideration of all reasonably foreseeable exposure pathways for a particular chemical. The consideration of all potential exposure pathways for some commonly used chemicals presents a daunting challenge for the exposure assessor. This article presents a framework for managing this complicated process, and illustrates the application of the framework with a hypothetical case study. The framework provides guidance for interpreting multiple sources of exposure information and developing a plausible list of exposure pathways for a chemical. Furthermore, the framework provides a means to process all the available information to eliminate pathways of negligible concern from consideration. Finally, the framework provides guidance for utilizing the tiered approach of VCCEP to efficiently conduct an assessment by first using simple, screening-level approaches and then, if necessary, using more complex, refined exposure assessment methods. The case study provides an illustration of the major concepts.

An ecological risk assessment for triclosan in lotic systems following discharge from wastewater treatment plants in the United States.

A modeling study was conducted to examine the distribution of concentrations of the antimicrobial triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) in rivers following discharge from wastewater treatment plants (WWTPs). Most uses of triclosan are disposed of down residential drains and ultimately reach WWTPs. A modeling analysis was conducted to simulate the discharge of triclosan in WWTP effluents to rivers and calculate the expected concentrations based on characteristics of the reach where the discharge occurred, the estimated concentration of triclosan in the WWTP effluent, and the physicochemical properties of triclosan. A probabilistic exposure assessment was conducted based on data on the characteristics of U.S. reaches receiving wastewater discharges and the physicochemical characteristics of triclosan. A risk assessment was conducted by comparing the estimated concentrations with toxicity endpoint concentrations for species representative of key ecological groups. For fish and invertebrates, neither acute nor chronic risks are of concern, and no concerns exist for vascular aquatic plants. However, certain types of algae are the most sensitive species to triclosan by more than an order of magnitude than other algal or aquatic plant species. For these algae, the potential exists for some risk from triclosan exposure near the WWTP discharge location during low-flow-rate periods for some WWTPs with small dilutions. The risks downstream are lower because of dissipation of triclosan.