Hormesis: A Conversation with a Critic

Objective

In this commentary I respond to points raised in the commentary by Mushak [Ad hoc and fast forward: the science and control of hormesis growth and development. Environ Health Perspect 117:1333–1338 (2009)], which principally concerns studies by me and my colleagues concerning the frequency of hormesis in toxicology.

Discussion

In this commentary I demonstrate that Mushak’s analysis contains critical statistical errors and misunderstandings of statistical concepts that invalidate its conclusions concerning the frequency of hormesis in the toxicologic literature.

Conclusions

In his commentary Mushak offers no significant new conceptual insights, and his key technical criticisms of hormesis frequency findings are unfounded.     

A Novel Approach Using DNA-Repair–Deficient Chicken DT40 Cell Lines for Screening and Characterizing the Genotoxicity of Environmental Contaminants

Background

Many bacterial or mammalian cell-based test systems, such as the Ames test, chromosomal aberration assays, or gene mutation assays, are commonly used in developed countries to detect the genotoxicity of industrial chemicals. However, the specificity is generally limited and the sensitivity is not sufficiently high. In addition, most assays cannot provide information on mechanisms of genotoxicity of a given chemical.

Objectives

We aimed to establish a sensitive and fast screening method that is also capable of characterizing mechanisms of genotoxicity.

Methods

We developed a novel bioassay employing gene-disrupted clones of the chicken DT40 B-lymphocyte line, which are designed to be deficient in several specific DNA repair pathways. Genotoxic chemicals can delay cellular proliferation in DNA-repair–deficient clones more significantly than in wild-type cells by interfering with DNA replication, thereby inducing DNA damage. In addition, we verified the validity of this assay by analyzing the genotoxicity of γ-rays, ultraviolet (UV) light, and sodium metaarsenite (NaAsO₂). We also characterized DNA lesions induced by NaAsO₂.

Results

Genotoxicity of given stressors was successfully screened based on a comparison of proliferation kinetics between wild-type and DNA-repair–deficient mutants in 48 hr. We also found that NaAsO₂ apparently induces at least two types of damage: chromosomal breaks and UV photoproduct-like DNA lesions.

Conclusion

This bioassay is a reliable and sensitive screening tool for environmental mutagens as well as for further characterizing the nature of detected genotoxicity.     

Meeting report: Estimating the benefits of reducing hazardous air pollutants--summary of 2009 workshop and future considerations

Background

Quantifying the benefits of reducing hazardous air pollutants (HAPs, or air toxics) has been limited by gaps in toxicological data, uncertainties in extrapolating results from high-dose animal experiments to estimate human effects at lower doses, limited ambient and personal exposure monitoring data, and insufficient economic research to support valuation of the health impacts often associated with exposure to individual air toxics.

Objectives

To address some of these issues, the U.S. Environmental Protection Agency held the Workshop on Estimating the Benefits of Reducing Hazardous Air Pollutants (HAPs) in Washington, DC, from 30 April to 1 May 2009.

Discussion

Experts from multiple disciplines discussed how best to move forward on air toxics benefits assessment, with a focus on developing near-term capability to conduct quantitative benefits assessment. Proposed methodologies involved analysis of data-rich pollutants and application of this analysis to other pollutants, using dose–response modeling of animal data for estimating benefits to humans, determining dose-equivalence relationships for different chemicals with similar health effects, and analysis similar to that used for criteria pollutants. Limitations and uncertainties in economic valuation of benefits assessment for HAPS were discussed as well.

Conclusions

These discussions highlighted the complexities in estimating the benefits of reducing air toxics, and participants agreed that alternative methods for benefits assessment of HAPs are needed. Recommendations included clearly defining the key priorities of the Clean Air Act air toxics program to identify the most effective approaches for HAPs benefits analysis, focusing on susceptible and vulnerable populations, and improving dose–response estimation for quantification of benefits.     

Environmental Health Research and the Observer’s Dilemma

Background

Environmental health researchers frequently study people in occupational, educational, recreational, or domestic settings who are exposed to hazardous agents.

Objective/discussion

Deciding whether—and how—to inform research subjects about risks they face in their environment can be a challenging task for investigators. Because legal rules and professional guidelines do not cover this topic, investigators must carefully consider their ethical obligations in light of the facts and circumstances.

Conclusion

To navigate through this dilemma, investigators should consider the evidence for the risks, the nature of the risks, the usefulness of risk information to the subjects, and the effects on the study and community of informing subjects about risks.     

Enhancing credibility of chemical safety studies: emerging consensus on key assessment criteria

Objectives

We examined the extent to which consensus exists on the criteria that should be used for assessing the credibility of a scientific work, regardless of its funding source, and explored how these criteria might be implemented.

Data sources

Three publications, all presented at a session of the 2009 annual meeting of the Society for Risk Analysis, have proposed a range of criteria for evaluating the credibility of scientific studies. At least two other similar sets of criteria have recently been proposed elsewhere.

Data extraction/synthesis

In this article we review these criteria, highlight the commonalities among them, and integrate them into a list of 10 criteria. We also discuss issues inherent in any attempt to implement the criteria systematically.

Conclusions

Recommendations by many scientists and policy experts converge on a finite list of criteria for assessing the credibility of a scientific study without regard to funding source. These criteria should be formalized through a consensus process or a governmental initiative that includes discussion and pilot application of a system for reproducibly implementing them. Formal establishment of such a system should enable the debate regarding chemical studies to move beyond funding issues and focus on scientific merit.     

Global Burden of Aflatoxin-Induced Hepatocellular Carcinoma: A Risk Assessment

Background

Hepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide, with prevalence 16–32 times higher in developing countries than in developed countries. Aflatoxin, a contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus in maize and nuts, is a known human liver carcinogen.

Objectives

We sought to determine the global burden of HCC attributable to aflatoxin exposure.

Methods

We conducted a quantitative cancer risk assessment, for which we collected global data on food-borne aflatoxin levels, consumption of aflatoxin-contaminated foods, and hepatitis B virus (HBV) prevalence. We calculated the cancer potency of aflatoxin for HBV-postive and HBV-negative individuals, as well as the uncertainty in all variables, to estimate the global burden of aflatoxin-related HCC.

Results

Of the 550,000–600,000 new HCC cases worldwide each year, about 25,200–155,000 may be attributable to aflatoxin exposure. Most cases occur in sub-Saharan Africa, Southeast Asia, and China where populations suffer from both high HBV prevalence and largely uncontrolled aflatoxin exposure in food.

Conclusions

Aflatoxin may play a causative role in 4.6–28.2% of all global HCC cases.     

Workplace Exposures and the Risk of Amyotrophic Lateral Sclerosis

Background

Occupation has been suggested to play a role in amyotrophic lateral sclerosis (ALS) etiology, but detailed information on the importance of specific workplace exposures is lacking.

Objectives

Our aim was to assess the relationship between workplace exposures and the risk of ALS and to evaluate potential interactions between these exposures and smoking.

Methods

We conducted a case–control study in New England between 1993 and 1996, comprising 109 cases and 253 controls who completed a structured interview covering occupations and workplace exposures. Unconditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for ALS. Analyses were conducted among the entire study population and after stratification by smoking.

Results

We observed a higher risk of ALS for construction workers excluding supervisors (OR = 2.9; 95% CI, 1.2–7.2) and precision metal workers (OR = 3.5; 95% CI, 1.2–10.5). Self-reported exposures to paint strippers; cutting, cooling, or lubricating oils; antifreeze or coolants; mineral or white spirits; and dry cleaning agents each appeared to be associated with a 60–90% higher risk. Specific chemicals related to a > 50% increase in risk of ALS included aliphatic chlorinated hydrocarbons, glycols, glycol ethers, and hexane. Relative risks associated with these workplace exposures and chemicals were greater among nonsmokers and persisted in mutually adjusted models.

Conclusions

Our data suggest that certain occupations and workplace exposures may be associated with increased risk of ALS. These results need to be confirmed in independent populations.     

The Precautionary Principle in the Context of Mobile Phone and Base Station Radiofrequency Exposures

Background

No health hazard has been established from exposure to radiofrequency fields up to the levels recommended by the International Commission on Non-Ionizing Radiation Protection. However, in response to public concern and the perceived level of scientific uncertainty, there are continuing calls for the application of the precautionary principle to radiofrequency exposures from mobile phones and base stations.

Objective

We examined the international evolution of calls for precautionary measures in relation to mobile phones and base stations, with particular focus on Australia and the United Kingdom.

Results

The precautionary principle is difficult to define, and there is no widespread agreement as to how it should be implemented. However, there is a strong argument that precautionary measures should not be implemented in the absence of reliable scientific data and logical reasoning pointing to a possible health hazard. There is also experimental evidence that precautionary advice may increase public concern.

Conclusion

We argue that conservative exposure standards, technical features that minimize unnecessary exposures, ongoing research, regular review of standards, and availability of consumer information make mobile communications inherently precautionary. Commonsense measures can be adopted by individuals, governments, and industry to address public concern while ensuring that mobile networks are developed for the benefit of society.     

Environmental Health Indicators of Climate Change for the United States: Findings from the State Environmental Health Indicator Collaborative

Objective

To develop public health adaptation strategies and to project the impacts of climate change on human health, indicators of vulnerability and preparedness along with accurate surveillance data on climate-sensitive health outcomes are needed. We researched and developed environmental health indicators for inputs into human health vulnerability assessments for climate change and to propose public health preventative actions.

Data sources

We conducted a review of the scientific literature to identify outcomes and actions that were related to climate change. Data sources included governmental and nongovernmental agencies and the published literature.

Data extraction

Sources were identified and assessed for completeness, usability, and accuracy. Priority was then given to identifying longitudinal data sets that were applicable at the state and community level.

Data synthesis

We present a list of surveillance indicators for practitioners and policy makers that include climate-sensitive health outcomes and environmental and vulnerability indicators, as well as mitigation, adaptation, and policy indicators of climate change.

Conclusions

A review of environmental health indicators for climate change shows that data exist for many of these measures, but more evaluation of their sensitivity and usefulness is needed. Further attention is necessary to increase data quality and availability and to develop new surveillance databases, especially for climate-sensitive morbidity.     

Biomonitoring Data for 2,4-Dichlorophenoxyacetic Acid in the United States and Canada: Interpretation in a Public Health Risk Assessment Context Using Biomonitoring Equivalents

Background

Several extensive studies of exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) using urinary concentrations in samples from the general population, farm applicators, and farm family members are now available. Reference doses (RfDs) exist for 2,4-D, and Biomonitoring Equivalents (BEs; concentrations in urine or plasma that are consistent with those RfDs) for 2,4-D have recently been derived and published.

Objective

We reviewed the available biomonitoring data for 2,4-D from the United States and Canada and compared them with BE values to draw conclusions regarding the margin of safety for 2,4-D exposures within each population group.

Data sources

Data on urinary 2,4-D excretion in general and target populations from recent published studies are tabulated and the derivation of BE values for 2,4-D summarized.

Data synthesis

The biomonitoring data indicate margins of safety (ratio of BE value to biomarker concentration) of approximately 200 at the central tendency and 50 at the extremes in the general population. Median exposures for applicators and their family members during periods of use appear to be well within acute exposure guidance values.

Conclusions

Biomonitoring data from these studies indicate that current exposures to 2,4-D are below applicable exposure guidance values. This review demonstrates the value of biomonitoring data in assessing population exposures in the context of existing risk assessments using the BE approach. Risk managers can use this approach to integrate the available biomonitoring data into an overall assessment of current risk management practices for 2,4-D.     

Biomonitoring Studies Should Be Used by Regulatory Agencies to Assess Human Exposure Levels and Safety of Bisphenol A

Background

Within the past 3 years, four major evaluations of bisphenol A (BPA) safety have been undertaken. However, these assessments have arrived at quite different conclusions regarding the safety of BPA at current human exposure levels.

Objectives

We compared the reasons provided by the European Food Safety Authority (EFSA) BPA risk assessment panel for their conclusion that human exposures are negligible with the conclusions reached by the other panels, with all panels having the same body of literature at their disposal.

Discussion

The EFSA panel dismissed ≥ 80 biomonitoring studies that documented significant levels of BPA exposure in humans, including internal exposures to unconjugated BPA, on the basis that they did not match a model of BPA metabolism. Instead, the EFSA panel relied on two toxicokinetic studies—conducted in 15 adults administered BPA—to draw conclusions about exposure levels in the population, including exposures of neonates.

Conclusions

As with all exposure assessments, models should be developed to explain actual data that are collected. In the case of BPA, samples from a large number of human subjects clearly indicate that humans are internally exposed to unconjugated BPA. The dismissal of these biomonitoring studies simply because their results do not conform to a model violates scientific principles. Expert panels should evaluate all data—including human biomonitoring studies—to make informed risk assessments.     

Using Systematic Reviews and Meta-Analyses to Support Regulatory Decision Making for Neurotoxicants: Lessons Learned from a Case Study of PCBs

Background

Epidemiologic weight-of-evidence reviews to support regulatory decision making regarding the association between environmental chemical exposures and neurodevelopmental outcomes in children are often complicated by lack of consistency across studies.

Objective

We examined prospective cohort studies evaluating the relation between prenatal and neonatal exposure to polychlorinated biphenyls (PCBs) and neurodevelopment in children to assess the feasibility of conducting a meta-analysis to support decision making.

Data extraction/synthesis

We described studies in terms of exposure and end point categorization, statistical analysis, and reporting of results. We used this evaluation to assess the feasibility of grouping studies into reasonably uniform categories.

Results

The current literature includes 11 cohorts of children for whom effects from prenatal or neonatal PCB exposures were assessed. The most consistently used tests included Brazelton’s Neonatal Behavioral Assessment Scale, the neurologic optimality score in the neonatal period, the Bayley Scales of Infant Development at 5–8 months of age, and the McCarthy Scales of Children’s Abilities in 5-year-olds. Despite administering the same tests at similar ages, the studies were too dissimilar to allow a meaningful quantitative examination of outcomes across cohorts.

Conclusions

These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability. Our findings add support to previous calls for establishing consensus standards for the conduct, analysis, and reporting of epidemiologic studies in general, and for those evaluating the effects of potential neurotoxic exposures in particular.     

In-Home Coal and Wood Use and Lung Cancer Risk: A Pooled Analysis of the International Lung Cancer Consortium

Background

Domestic fuel combustion from cooking and heating is an important public health issue because roughly 3 billion people are exposed worldwide. Recently, the International Agency for Research on Cancer classified indoor emissions from household coal combustion as a human carcinogen (group 1) and from biomass fuel (primarily wood) as a probable human carcinogen (group 2A).

Objectives

We pooled seven studies from the International Lung Cancer Consortium (5,105 cases and 6,535 controls) to provide further epidemiological evaluation of the association between in-home solid-fuel use, particularly wood, and lung cancer risk.

Methods

Using questionnaire data, we classified subjects as predominant solid-fuel users (e.g., coal, wood) or nonsolid-fuel users (e.g., oil, gas, electricity). Unconditional logistic regression was used to estimate the odds ratios (ORs) and to compute 95% confidence intervals (CIs), adjusting for age, sex, education, smoking status, race/ethnicity, and study center.

Results

Compared with nonsolid-fuel users, predominant coal users (OR = 1.64; 95% CI, 1.49–1.81), particularly coal users in Asia (OR = 4.93; 95% CI, 3.73–6.52), and predominant wood users in North American and European countries (OR = 1.21; 95% CI, 1.06–1.38) experienced higher risk of lung cancer. The results were similar in never-smoking women and other subgroups.

Conclusions

Our results are consistent with previous observations pertaining to in-home coal use and lung cancer risk, support the hypothesis of a carcinogenic potential of in-home wood use, and point to the need for more detailed study of factors affecting these associations.     

Urinary,Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

Background

Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies.

Objective

We examined several possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions.

Data sources

We examined > 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism.

Data extraction and synthesis

The > 80 biomonitoring studies examined included measurements in thousands of individuals from several different countries, and these studies overwhelmingly detected BPA in individual adults, adolescents, and children. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Some regulatory agencies have relied solely on these toxicokinetic models in their risk assessments.

Conclusions

Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.     

Climate Variability and Hemorrhagic Fever with Renal Syndrome Transmission in Northeastern China

Background

The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by climatic variables. However, few studies have examined the quantitative relationship between climate variation and HFRS transmission.

Objective

We examined the potential impact of climate variability on HFRS transmission and developed climate-based forecasting models for HFRS in northeastern China.

Methods

We obtained data on monthly counts of reported HFRS cases in Elunchun and Molidawahaner counties for 1997–2007 from the Inner Mongolia Center for Disease Control and Prevention and climate data from the Chinese Bureau of Meteorology. Cross-correlations assessed crude associations between climate variables, including rainfall, land surface temperature (LST), relative humidity (RH), and the multivariate El Niño Southern Oscillation (ENSO) index (MEI) and monthly HFRS cases over a range of lags. We used time-series Poisson regression models to examine the independent contribution of climatic variables to HFRS transmission.

Results

Cross-correlation analyses showed that rainfall, LST, RH, and MEI were significantly associated with monthly HFRS cases with lags of 3–5 months in both study areas. The results of Poisson regression indicated that after controlling for the autocorrelation, seasonality, and long-term trend, rainfall, LST, RH, and MEI with lags of 3–5 months were associated with HFRS in both study areas. The final model had good accuracy in forecasting the occurrence of HFRS.

Conclusions

Climate variability plays a significant role in HFRS transmission in northeastern China. The model developed in this study has implications for HFRS control and prevention.     

Association between Rainfall and Pediatric Emergency Department Visits for Acute Gastrointestinal Illness

Background

Microbial water contamination after periods of heavy rainfall is well described, but its link to acute gastrointestinal illness (AGI) in children is not well known.

Objectives

We hypothesize an association between rainfall and pediatric emergency department (ED) visits for AGI that may represent an unrecognized, endemic burden of pediatric disease in a major U.S. metropolitan area served by municipal drinking water systems.

Methods

We conducted a retrospective time series analysis of visits to the Children’s Hospital of Wisconsin ED in Wauwatosa, Wisconsin. Daily visit totals of discharge International Classification of Diseases, 9th Revision codes of gastroenteritis or diarrhea were collected along with daily rainfall totals during the study period from 2002 to 2007. We used an autoregressive moving average model, adjusting for confounding variables such as sewage release events and season, to look for an association between daily visits and rainfall after a lag of 1–7 days.

Results

A total of 17,357 AGI visits were identified (mean daily total, 7.9; range, 0–56). Any rainfall 4 days prior was significantly associated with an 11% increase in AGI visits. Expected seasonal effects were also seen, with increased AGI visits in winter months.

Conclusions

We observed a significant association between rainfall and pediatric ED visits for AGI, suggesting a waterborne component of disease transmission in this population. The observed increase in ED visits for AGI occurred in the absence of any disease outbreaks reported to public health officials in our region, suggesting that rainfall-associated illness may be underestimated. Further study is warranted to better address this association.     

Evaluation of Spatial Relationships between Health and the Environment: The Rapid Inquiry Facility

Background

The initiation of environmental public health tracking systems in the United States and the United Kingdom provided an opportunity to advance techniques and tools available for spatial epidemiological analysis integrating both health and environmental data.

Objective

The Rapid Inquiry Facility (RIF) allows users to calculate adjusted and unadjusted standardized rates and risks. The RIF is embedded in ArcGIS so that further geographical information system (GIS) spatial functionality can be exploited or results can be exported to statistical packages for further tailored analyses where required. The RIF also links directly to several statistical packages and displays the results in the GIS.

Methods

The value of the RIF is illustrated here with two case studies: risk of leukemia in areas surrounding oil refineries in the State of Utah (USA) and an analysis of the geographical variation of risk of esophageal cancer in relation to zinc cadmium sulfide exposure in Norwich (United Kingdom).

Results

The risk analysis study in Utah did not suggest any evidence of increased relative risk of leukemia, multiple myeloma, or Hodgkin’s lymphoma in the populations around the five oil-refining facilities but did reveal an excess risk of non-Hodgkin’s lymphoma that might warrant further investigation. The disease-mapping study in Norwich did not reveal any areas with higher relative risks of esophageal cancer common to both males and females, suggesting that a common geographically determined exposure was unlikely to be influencing cancer risk in the area.

Conclusion

The RIF offers a tool that allows epidemiologists to quickly carry out ecological environmental epidemiological analysis such as risk assessment or disease mapping.     

Chemical Contamination of Green Turtle (Chelonia mydas) Eggs in Peninsular Malaysia: Implications for Conservation and Public Health

Background

Persistent organic pollutants (POPs)—such as organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs)—and heavy metals have been reported in sea turtles at various stages of their life cycle. These chemicals can disrupt development and function of wildlife. Furthermore, in areas such as Peninsular Malaysia, where the human consumption of sea turtle eggs is prevalent, egg contamination may also have public health implications.

Objective

In the present study we investigated conservation and human health risks associated with the chemical contamination of green turtle (Chelonia mydas) eggs in Peninsular Malaysia.

Methods

Fifty-five C. mydas eggs were collected from markets in Peninsular Malaysia and analyzed for POPs and heavy metals. We conducted screening risk assessments (SRAs) and calculated the percent of acceptable daily intake (ADI) for POPs and metals to assess conservation and human health risks associated with egg contamination.

Results

C. mydas eggs were available in 9 of the 33 markets visited. These eggs came from seven nesting areas from as far away as Borneo Malaysia. SRAs indicated a significant risk to embryonic development associated with the observed arsenic concentrations. Furthermore, the concentrations of coplanar PCBs represented 3 300 times the ADI values set by the World Health Organization.

Conclusions

The concentrations of POPs and heavy metals reported in C. mydas eggs from markets in Peninsular Malaysia pose considerable risks to sea turtle conservation and human health.     

Guidelines to Evaluate Human Observational Studies for Quantitative Risk Assessment

Background

Careful evaluation of the quality of human observational studies (HOS) is required to assess the suitability of HOS for quantitative risk assessment (QRA). In particular, the quality of quantitative exposure assessment is a crucial aspect of HOS to be considered for QRA.

Objective

We aimed to develop guidelines for the evaluation of HOS for QRA and to apply these guidelines to case–control and cohort studies on the relation between exposure to benzene and acute myeloid leukemia (AML).

Methods

We developed a three-tiered framework specific for the evaluation of HOS for QRA and used it to evaluate HOS on the relation between exposure to benzene and AML.

Results

The developed framework consists of 20 evaluation criteria. A specific focus of the framework was on the quality of exposure assessment applied in HOS. Seven HOS on the relation of benzene and AML were eligible for evaluation. Of these studies, five were suitable for QRA and were ranked based on the quality of the study design, conduct, and reporting on the study.

Conclusion

The developed guidelines facilitate a structured evaluation that is transparent in its application and harmonizes the evaluation of HOS for QRA. With the application of the guidelines, it was possible to identify studies suitable for QRA of benzene and AML and rank these studies based on their quality. Application of the guidelines in QRA will be a valuable addition to the assessment of the weight of evidence of HOS for QRA.     

The Implications of Using a Physiologically Based Pharmacokinetic (PBPK) Model for Pesticide Risk Assessment

Background

A physiologically based pharmacokinetic (PBPK) model would make it possible to simulate the dynamics of chemical absorption, distribution, metabolism, and elimination (ADME) from different routes of exposures and, in theory, could be used to evaluate associations between exposures and biomarker measurements in blood or urine.

Objective

We used a PBPK model to predict urinary excretion of 3,5,6-trichloro-2-pyridinol (TCPY), the specific metabolite of chlorpyrifos (CPF), in young children.

Methods

We developed a child-specific PBPK model for CPF using PBPK models previously developed for rats and adult humans. Data used in the model simulation were collected from 13 children 3–6 years of age who participated in a cross-sectional pesticide exposure assessment study with repeated environmental and biological sampling.

Results

The model-predicted urinary TCPY excretion estimates were consistent with measured levels for 2 children with two 24-hr duplicate food samples that contained 350 and 12 ng/g of CPF, respectively. However, we found that the majority of model outputs underpredicted the measured urinary TCPY excretion.

Conclusions

We concluded that the potential measurement errors associated with the aggregate exposure measurements will probably limit the applicability of PBPK model estimates for interpreting urinary TCPY excretion and absorbed CPF dose from multiple sources of exposure. However, recent changes in organophosphorus (OP) use have shifted exposures from multipathways to dietary ingestion only. Thus, we concluded that the PBPK model is still a valuable tool for converting dietary pesticide exposures to absorbed dose estimates when the model input data are accurate estimates of dietary pesticide exposures.