Iodine supplementation and drinking-water perchlorate mitigation.

Ensuring adequate iodine intake is important, particularly among women of reproductive age, because iodine is necessary for early life development. Biologically based dose-response modeling of the relationships among iodide status, perchlorate dose, and thyroid hormone production in pregnant women has indicated that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia. We evaluated the possibility of increasing iodine intake to offset potential risks from perchlorate exposure. We also explored the effect of dietary exposures to nitrate and thiocyanate on iodine uptake and thyroid hormone production. Our modeling indicates that the level of thyroid hormone perturbation associated with perchlorate exposures in the range of current regulatory limits is extremely small and would be overwhelmed by other goitrogen exposures. Our analysis also shows that microgram levels of iodine supplementation would be sufficient to prevent the goitrogenic effects of perchlorate exposure at current regulatory limits among at risk individuals. The human health risks from supplementing drinking water with iodine are negligible; therefore, this approach is worthy of regulatory consideration.

Improving weight of evidence approaches to chemical evaluations.

Federal and other regulatory agencies often use or claim to use a weight of evidence (WoE) approach in chemical evaluation. Their approaches to the use of WoE, however, differ significantly, rely heavily on subjective professional judgment, and merit improvement. We review uses of WoE approaches in key articles in the peer-reviewed scientific literature, and find significant variations. We find that a hypothesis-based WoE approach, developed by Lorenz Rhomberg et al., can provide a stronger scientific basis for chemical assessment while improving transparency and preserving the appropriate scope of professional judgment. Their approach, while still evolving, relies on the explicit specification of the hypothesized basis for using the information at hand to infer the ability of an agent to cause human health impacts or, more broadly, affect other endpoints of concern. We describe and endorse such a hypothesis-based WoE approach to chemical evaluation.

Toxicity testing in the 21st century: a vision and a strategy.

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

A margin-of-exposure approach to assessment of noncancer risks of dioxins based on human exposure and response data.

BACKGROUND: Risk assessment of human environmental exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs) and other dioxin-like compounds is complicated by several factors, including limitations in measuring intakes because of the low concentrations of these compounds in foods and the environment and interspecies differences in pharmacokinetics and responses. OBJECTIVES: We examined the feasibility of relying directly on human studies of exposure and potential responses to PCDD/PCDFs and related compounds in terms of measured lipid-adjusted concentrations to assess margin of exposure (MOE) in a quantitative, benchmark dose (BMD)-based framework using representative exposure and selected response data sets. METHODS: We characterize estimated central tendency and upper-bound general U.S. population lipid-adjusted concentrations of PCDD/PCDFs from the 1970s and early 2000s based on available data sets. Estimates of benchmark concentrations for three example responses of interest (induction of cytochrome P4501A2 activity, dental anomalies, and neonatal thyroid hormone alterations) were derived based on selected human studies. RESULTS: The exposure data sets indicate that current serum lipid concentrations in young adults are approximately 6- to 7-fold lower than 1970s-era concentrations. Estimated MOEs for each end point based on current serum lipid concentrations range from < 10 for neonatal thyroid hormone concentrations to > 100 for dental anomalies-approximately 6-fold greater than would have existed during the 1970s. CONCLUSIONS: Human studies of dioxin exposure and outcomes can be used in a BMD framework for quantitative assessments of MOE. Incomplete exposure characterization can complicate the use of such studies in a BMD framework.

Assessing and managing methylmercury risks associated with power plant mercury emissions in the United States.

Until the Clean Air Mercury Rule was signed in March 2005, coal-fired electric utilities were the only remaining, unregulated major source of industrial mercury emissions in the United States. Proponents of coal-burning power plants assert that methylmercury is not a hazard at the current environmental levels, that current technologies for limiting emissions are unreliable, and that reducing mercury emissions from power plants in the United States will have little impact on environmental levels. Opponents of coal-burning plants assert that current methylmercury exposures from fish are damaging to the developing nervous system of infants, children, and the fetus; that current technology can significantly limit emissions; and that reducing emissions will reduce exposure and risk. One concern is that local mercury emissions from power plants may contribute to higher local exposure levels, or "hot spots." The impact of the Mercury Rule on potential hot spots is uncertain due to the highly site-specific nature of the relationship between plant emissions and local fish methylmercury levels. The impact on the primary source of exposure in the United States, ocean fish, is likely to be negligible due to the contribution of natural sources and industrial sources outside the United States. Another debate centers on the toxic potency of methylmercury, with the scientific basis of the US Environmental Protection Agency's (EPA's) recommended exposure limit questioned by some and defended by others. It is likely that the EPA's exposure limit may be appropriate for combined exposure to methylmercury and polychlorinated biphenyls (PCBs), but may be lower than the available data suggest is necessary to protect children from methylmercury alone. Mercury emissions from power plants are a global problem. Without a global approach to developing and implementing clean coal technologies, limiting US power plant emissions alone will have little impact.

Overview of exposure, toxicity, and risks to children from current levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds in the USA.

Studies of children indicate that exposure of the general population to low levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) does not result in any clinical evidence of disease, although accidental exposure to high levels either before or after birth have led to a number of developmental deficits. Breast-fed infants have higher exposures than formula-fed infants, but studies consistently find that breast-fed infants perform better on developmental neurologic tests than their formula-fed counterparts, supporting the well-recognized benefits of breast feeding. Children receive higher exposures to PCDD/Fs from food than adults on a body-weight basis but those exposures are below the World Health Organization's tolerable daily intake. Laboratory rodents appear to be at least an order of magnitude more sensitive than humans to the aryl hydrocarbon receptor-mediated effects of these substances, which makes them poor surrogates for predicting quantitative risks but makes them good models for establishing safe levels of human exposure by organizations mandated to protect public health. Any exposure limit for PCDD/Fs based on developmental toxicity in sensitive laboratory animals can be expected to be especially protective of human health, including the health of infants and children. Because body burdens and environmental levels continue to decline, it is unlikely that children alive today in the USA will experience exposures to PCDD/Fs that are injurious to their health.

Symposium summary: children's health risk--what's so special about the developing immune system?

In recent years, there has been increasing regulatory pressure to protect the health of children, with the basic tenet being that children differ significantly from adults in their biological or physiological responses to chemical exposures. In a regulatory context, this has been translated to mean a requirement for an additional 10-fold safety factor for environmental contaminants, specialized tests, or both. Much of the initial focus has been on the developing endocrine and nervous systems; but increasingly, the developing immune system has been identified as a potential target organ for chemically mediated toxicity. More recently, the question has been raised regarding whether the current state of science supports the creation of developmental immunotoxicology (DIT) test guidelines. What is needed is a risk-based evaluation of the biology associated with the proposed differential sensitivity between children and adults and the impact of that assessment on additional regulatory measures to protect children in risk assessment analyses. Additionally, an understanding of whether the developing immune system shows greater susceptibility, either qualitatively or quantitatively, to chemical perturbation is critical. To address the question "What's so special about the developing immune system?" a symposium was organized for the 2003 Society of Toxicology annual meeting that brought together risk assessors, clinicians, immunologists, and toxicologists.

Review of procedures for protecting human subjects in recent clinical studies of pesticides.

Arguments have been made for and against the regulatory use of data from human subjects on both scientific and ethical grounds. One argument against the use of data from human clinical studies involving pesticides asserts that such data are obtained from studies that do not follow the Common Rule (40 CFR 26), which provides procedures for protecting human subjects in studies funded by federal agencies, including the U.S. Environmental Protection Agency (U.S. EPA). Although privately conducted studies using human subjects are not legally subject to or required to comply with the Common Rule, the protections of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice are commonly followed. We sought to answer the question of whether recent human clinical studies with insecticides performed according to Good Clinical Practice provided volunteers with the same protections as the Common Rule. All three sets of guidance have in common the intent to protect volunteer human subjects by providing standards for the conduct of studies in which they participate. This analysis compares the elements of the Common Rule with comparable elements from the Declaration of Helsinki and Good Clinical Practice to evaluate similarities and differences in procedural requirements. It then evaluates the documentation from 15 recent human studies of twelve insecticides conducted at four clinical laboratories in order to determine whether the conduct of those studies is consistent with the protections of the Common Rule. There were some cases for which we could not verify compliance with certain Common Rule elements; however, based on our evaluation it is apparent that the studies we reviewed were conducted in a manner substantially consistent with the fundamental protections of the Common Rule-voluntary participation, informed consent, and review by an ethical committee or institutional review board.

Di-alkyl phosphate biomonitoring data: assessing cumulative exposure to organophosphate pesticides.

The 1996 Food Quality Protection Act (FQPA) requires the evaluation of both aggregate and cumulative health risks from pesticides (FFDCA 408(b)(2)(D)(v) and (vi).) Organophosphate (OP) pesticides are the first class of chemicals to undergo FQPA mandated aggregate and cumulative assessments. In this report, summary data on biomonitoring for urinary levels of six alkyl phosphate (AP) metabolites of OPs, as reported in the initial, March 2001, U.S. Centers for Disease Control and Prevention's (CDC) "National Report on Human Exposure to Environmental Chemicals," are compared to EPA modeled estimates of OP exposure reported in Registration Eligibility Decision documents (REDs), Interim REDs and to currently reported cumulative exposure estimates in the EPA's Cumulative Risk Assessment of the Organophosphate Pesticides. This comparison indicates that EPA's aggregate exposure estimates (dietary, drinking water, and non-dietary residential exposures) for many individual OPs were greater than the cumulative estimate for all OPs combined based on the CDC AP biomonitoring data. The results also suggest that EPA's screening level assessments of OPs, while being qualitative indicators of the relative importance of various exposure sources, are not good quantitative indicators of actual exposures. However, the mean biomonitoring estimate of cumulative OP exposure appears to exceed the EPA's subsequent preliminary estimate of cumulative OP exposure by as much as the REDs appear to overestimate the biomonitoring results. While the conservatism, tendency to overestimate exposure, in the individual REDs is readily acknowledged, the conservatism and limitations of applying currently available CDC AP biomonitoring data to evaluate human exposure to OPs are not as readily apparent. We postulate that oral absorption of non-anti cholinergic, pre-hydrolyzed OPs, sources of APs other than pesticides, and the conservative result of summing exposure from each AP at the geometric mean contribute to non-quantified overestimates of absorbed dosage from the CDC biomonitoring data reported in March 2001. CDC AP biomonitoring data may serve a useful purpose in providing an upper bound estimate of absorbed dosage for "ground truthing" aggregate exposure estimated from first tier models used in REDs, but at best may provide only a credible "target" for the complex cumulative exposure assessment models currently under development. The reliability of quantitative estimates of OP exposure levels will improve as cumulative risk exposure models are validated over time and under use conditions prevalent at the time the AP biomonitoring samples are collected. Analyses contained herein should be revisited and compared to the CDC Second National Report on Human Exposure to Environmental Chemicals ( http://www.cdc.gov/exposurereport), released to the public on January 31, 2003, and the final EPA OP Cumulative Risk Assessment.

Differential sensitivity of children and adults to chemical toxicity. I. Biological basis.

Children, particularly neonates, can be biologically more sensitive to the same toxicant exposure on a body weight basis than adults. Current understanding of the rates of maturation of metabolic capability and evidence from case examples on pharmaceuticals, drugs of abuse, environmental contaminants, and dietary and endogenous agents indicate that human infants up to approximately 6 months of age are typically--but not always--more sensitive to chemical toxicity than adults. For most chemicals, the immaturity of infant biotransformation, elimination, and other physiologic systems usually produces higher blood levels for longer periods. There is metabolic capacity for most tested substances in the newborn, although it is quite low and immature for some chemicals. For some chemicals, unique metabolic pathways not available in the adult human can also be utilized by the newborn. The newborn's metabolic capacity rapidly matures and, by about 6 months of age, children are usually not more sensitive to chemical toxicity than adults. By then, most metabolic systems are reasonably mature, becoming almost completely capable by 1 year of age. In many cases children are less sensitive than adults. Whether children are at greater risk from chemical exposures is another question. Risk depends on both inherent sensitivity and exposure conditions. If chemical exposure levels remain below those capable of overwhelming a child's metabolic detoxification systems and producing toxicity, children will be at no greater risk than are adults. Children of all ages are still developing so even if they are exposed to chemicals at levels below those of adults, they may be at greater risk than adults. However, as long as those exposure levels are still below those required to produce toxicity, children will not be at greater risk.

Differential sensitivity of children and adults to chemical toxicity. II. Risk and regulation.

Animals can be useful predictors of chemical hazards to humans. Growth and development are compressed into a shorter period in animals, which makes interpretation of animal testing inherently more difficult. However, similar events occur in both humans and laboratory animals and testing that covers the full period of animal development can reasonably be considered an appropriate surrogate for human development. Some have proposed an additional 10-fold factor for the extra protection of children when estimating safe exposures. Use of such an additional factor, as required by the Food Quality Protection Act (FQPA), is meant to address the same issues covered by the EPA's database uncertainty factor, UF(D), and additional issues related to exposure uncertainty. Thus, when UF(D) has already been deployed, the EPA modifies its use of the FQPA factor. Based on our analysis, we agree with the EPA. Drawing conclusions about the adequacy of UF(H), the uncertainty factor used to account for intrahuman variability, in terms of its ability to protect children on the basis of the modest data available is challenging. However, virtually all studies available suggest that a high percentage of the population, including children, is protected by using a 10-fold uncertainty factor for human variability or by using a 3.16-fold factor each for toxicokinetic and toxicodynamic variability. Based on specific comparisons for newborns, infants, children, adults, and those with severe disease, the population protected is between 60 and 100%, with the studies in larger populations that include sensitive individuals suggesting that the value is closer to 100%.