Chemical Mixtures: An Unsolvable Riddle?

It is difficult to overstate the complexity of assessing risks from chemical mixtures. For every valid reason to assess risks from mixtures, there appears an equally valid question as to whether it is possible to do so in a scientifically rigorous and relevant manner. Because so few data exist for mixtures, current mixture assessment methods must rely on untested assumptions and simplifications. That the accuracy of risk estimates improve with the number of chemicals assessed together as mixtures is a valid assumption only if assessment methods for mixtures are better than those based on individual chemicals. On the other hand, arbitrarily truncating a mixture assessment to make it manageable may lead to irrelevant risk estimates. Ideally, mixture assessments should be as broad as necessary to improve accuracy and reduce uncertainty over assessments that only use toxicity data for single chemicals. Further broadening the scope may be ill advised because of the tendency to increase rather than decrease uncertainty. Risk assessment methods that seek to be comprehensive at the expense of increased uncertainty can hardly be viewed as improvements. It would be prudent to verify that uncertainty can be reduced before burdening the risk assessment process with more complexity.     

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

We describe a set of criteria to evaluate the quality of data and interpretations in chemical interaction studies. These criteria reflect the consensus of the literature on interaction analysis developed over decades of research in pharmacology, toxicology, and biometry; address common pitfalls in published interaction studies; and can be easily applied to common methods of interaction analysis. The criteria apply broadly to interaction data for drugs, pesticides, industrial chemicals, food additives, and natural products and are intended to assist risk assessors who must evaluate interaction studies for use in component-based mixture risk assessments. The criteria may also assist researchers interested in conducting interaction studies to inform mixture risk assessment. The criteria are also intended to serve larger scientific goals, including increasing the repeatability of results obtained in chemical interaction studies, enhancing the reliability of conclusions drawn from interaction data, providing greater consistency of interpretations among various analysts, and decreasing uncertainty in using interaction data in risk assessments. We describe the basis for each criterion and demonstrate their utility by using them to evaluate interaction studies from the recent toxicological and pharmacological literature, which serve as examples of different types of data sets that the risk assessor may encounter.     

Health Risk Assessment of Chemical Mixtures Exposure to Residents in the Lake Taihu Region,China

This study assessed the mixture health risk for the residents of China's Lake Taihu region posed by a Persistent Organic Pollutants (POPs) mixture of dichloro-diphenyl-trichloroethane (DDT) and hexachlorocyclohexane (HCH). Multiple-pathway exposure models were used for exposure assessment in order to estimate the DDT and HCH exposure dose. The DDT and HCH PBPK models were developed and used for consequence assessment in order to analyze the pollutant distribution and accumulation process in human tissues. The tissue dose hazard index (HI) was used to estimate the mixture health risk. The results showed that the total exposure doses for male residents and female residents were 4.01 × 10^{? 4}～ 7.67 × 10^{? 3} mg/kg/day and 3.73 × 10^{? 4}～ 6.75 × 10^{? 3} mg/kg/day for DDT, respectively, and 3.78 × 10^{? 4}～ 5.14 × 10^{? 3} mg/kg/day and 3.53 × 10^{? 4}～ 4.66 × 10^{? 3} mg/kg/day for HCH, respectively. The maximum tissue concentrations in fat for male and female residents reached 110.51 mg/l and 97.21 mg/l for DDT, respectively, and 189.66 mg/l and 171.72 mg/l for HCH, respectively. The tissue dose hazard indexes for male and female residents were 0.1472 ～ 2.4990 and 0.1377 ～ 2.2230, respectively, and the probabilities of the risk exceeding the acceptable risk (HI = 1) for male and female were 24.60% and 16.51%, respectively.     

Environmental fate of the chemical mixtures: Crude oil,JP‐5, mineral spirits,and diesel fuel

Petroleum hydrocarbon mixtures in soils and groundwater present unique challenges in the estimation of potential human exposures and subsequent health risks. A major component of risk assessment affected by mixtures is the evaluation of environmental fate. The fate of petroleum mixtures may be evaluated by using either of three approaches: (1) the evaluation of the fate of indicator chemical(s), (2) the evaluation of the fate of the mixture as a whole with a surrogate, and (3) the evaluation of the fate of the hydrocarbon mixture as a whole. The limiting factor in the selection of an approach is the availability of information on specific chemical constituents in the mixture. The evaluation of environmental fate requires quantitative information regarding the distribution, mobility, and degradation/transformation as represented by various physicochemical properties. In addition to the availability of this information, the selection of the evaluation method should be consistent with the goals of the project, as each approach will produce different results. This presentation discusses the issues related to the identification and implementation of each of the approaches to the evaluation of the environmental fate of four petroleum mixtures (crude oil, JP‐5, mineral spirits, and diesel) for risk assessment purposes.     

An NGO Perspective on Risk Assessment and Scientific Research

Concerns over risk assessment have been raised by Non-Government Organizations (NGO) and the environmental community for decades. In considering proposals for research in this area, it is important for both scientists and policymakers to consider the following points: (1) risk assessment as a method of policymaking is increasingly inaccessible to meaningful public participation, (2) the lack of fundamental toxicological data constrains the application of risk assessment methods more than any other factor, and (3) the importance of individual susceptibility in risk assessments must be tempered by the lack of control over individual exposures.     

低剂量混合污染生态毒理与风险评价研究进展

环境中的化学品往往以低剂量混合形式存在.对单一化学品高剂量暴露下的生态毒性研究成果,难以适用于环境中低剂量混合物的生态毒理效应诊断及风险评价.文中概述了低剂量化学品混合污染生态毒理及风险评价方面的研究进展,主要包括低剂量化学品混合污染诊断的分子毒理研究方法、风险评价方法,并介绍了简单和复杂混合物的风险评价方案.对低剂量混合污染生态毒理与风险评价研究的发展动向提出了见解,指出低剂量化学混合物的研究需要寻找敏感终点,引入多学科手段,积累更多的数据,建立完善、统一的评价体系.     

Commentary: The Rôle of Toxicology in Prevention and Precaution

Advocates of the Precautionary Principle have recently called for a “new science” to support the goals of precaution-based environmental and occupational health policy. While much attention has been given to epidemiology, the evidentiary science most relevant to precaution, or prevention, is toxicology. Opportunities for enhancing the rôle of toxicology in public policy must consider current biases in the field. Thus, rather than a “new science,” advocates for change should focus upon ensuring that current scientific methods are appropriate and that interpretations of scientific data are accurate.     

Selected applications of reduced uncertainty factors in noncancer risk assessment

Guidelines have been developed within the Environmental Protection Agency (EPA) for applying uncertainty factors to noncancer risk assessments. In many recent cases, reduced values for uncertainty factors of less than 10 have been used. The specific circumstances that justify reduced uncertainty are: partial definition of the sensitive subpopulation among humans, partial database limitations, use of a minimal LOAEL, risk assessment for an essential nutrient, and risk assessments based upon studies in nonhuman primates. Details of the rationale for each of these circumstances are provided.     

Exploratory Cumulative Risk Assessment (CRA) Approaches Using Secondary Data

Cumulative risk assessments (CRAs) include the examination of risks posed by multiple stressors and include population-specific vulnerabilities and susceptibilities. In this case study, we assess potential hearing impairment hazard due to joint exposure from noise and volatile organic compounds (VOCs) in order to examine the strengths and limitations of using secondary data on exposure and health effects for a CRA. Block group-level noise categories were estimated using modeled street-level data. A quantile regression model of sociodemographic and personal predictors from the 1999–2000 U.S. National Health and Nutrition Examination Survey VOC dataset was used along with block group-level sociodemographic and personal variables to estimate VOC exposures. Hazard indices (HIs) for potential hearing impairment due to joint noise and VOC exposures were calculated. County-averaged HIs for hearing impairment ranged from 0.8 (10th total VOCs percentile and 45–60 dB) to 1.7 (90th total VOCs percentile and 71–75 dB). Limitations of the exposure and health effects data included issues combining heterogeneous data and a lack of established threshold levels for combined low-level exposures; yet, this case study illustrates that screening-level CRAs, including non-chemical stressors, can be accomplished with publicly available data and existing methods.     

A transgene-centered approach to the biosafety of transgenic phosphinothricin-tolerant plants

The microbial bar and pat genes confer tolerance to the non-selective herbicide phosphinothricin (PPT; sold as Basta or Finale). This tolerance in plants could provide an environmental gain compared to current-day herbicide cocktails, but the safety of such a transgene approach is questioned by many. The biosafety of the presence of these herbicide tolerance genes in plants is evaluated in a transgene-centered approach. Potentially, the introduction of transgenic PPT-tolerant crops could result in acquired PPT tolerance in weedy relatives of these crops. Assuming responsible use of this trait in agronomy, the ecological consequences with respect to weediness or spread of the transgenic PPT tolerance are concluded to be negligible. The key issue for the toxicological evaluation is whether or not the plant has actually been sprayed with PPT. Consumption of the gene and/or gene product from unsprayed transgenic plant material will not have adverse effects. In case of PPT-sprayed material, PPT or its derivatives could be present in food and feed and crop-specific metabolites might be formed. To date, the toxicological impact of such a putative exposure is not sufficiently clear, and further premarket testing is recommended.     

Effects of Metal Mixtures on Aquatic Biota: A Review of Observations and Methods

A brief review of the historical development of metal mixture interaction analyses is presented. The two major classifications of mixture models are outlined, the “Concentration Addition” and the “Response Addition” approaches. Within these two categories, a number of graphical, mathematical and statistical methods have been used, such as the toxic unit approach, relative potencies, toxicity equivalence factors, and dose-response relationships that have been described using several methods such as probit, logit, and regression analyses. A database was generated to evaluate the frequency of occurrence of less than additive, strictly additive, and more than additive responses to metal mixture effects reported in the literature. The three responses occurred at 43, 27, and 29%, respectively. The database is available electronically from the lead author. The research required to determine the most appropriate methods to quantify the effects of metal mixtures in an ecological risk assessment (ERA) framework is discussed. Until this research is completed, ERAs should use existing models such as the toxic unit or the effects addition approach. Bioaccumulation measurements by organisms for which the accumulation to response relationship is known would also be a useful complement.     

Environmental Risks of Inorganic Metals and Metalloids: A Continuing,Evolving Scientific Odyssey

Ecological risk assessment (ERA) of metals, metalloids, and inorganic metal substances (collectively referred to as metals) no longer focuses solely on persistence and bioaccumulation, but rather on solubility, toxicity, natural occurrence (concentrations above/added to background), essentiality (deficiency as well as excess), speciation, and bioavailability. Tolerance (both acclimation and adaptation) and possible resultant energetic costs are being considered, and realism is being increased in laboratory toxicity tests by the use of organisms pre-acclimated to natural levels of metals. The present status of ERAs for inorganic metals is summarized in terms of four key questions: (1) Do metals accumulate in biota above background levels? (2) Are these metals metabolically active? (3) If so, are they likely to result in adverse effects to individuals either alone or in combination with other stressors? (4) If so, are they likely to result in adverse impacts to populations? The most pragmatically useful future research will be that focused on the interactive risks of both complex chemical mixtures (metals and non-metals) and non-chemical stressors (both biotic and abiotic). Ideally this should occur in the context of continued metal loadings to terrestrial and aquatic ecosystems assessed holistically, including trophic food web relationships, metal transfer, and genetic diversity. Relationships between environmental concentrations and internal, metabolically active doses are the key to understanding and predicting environmental risks without excessive reliance on safety factors.     

Framework for validation and implementation of in vitro toxicity tests

Summary The development and application of in vitro alternatives designed to reduce or replace the use of animals, or to lessen the distress and discomfort of laboratory animals, is a rapidly developing trend in toxicology. However, at present there is no formal administrative process to organize, coordinate, or evaluate validation activities. A framework capable of fostering the validation of new methods is essential for the effective transfer of new technologic developments from the research laboratory into practical use. This committee has identified four essential validation resources: chemical bank(s), cell and tissue banks, a data bank, and reference laboratories. The creation of a Scientific Advisory Board composed of experts in the various aspects and endpoints of toxicity testing, and representing the academic, industrial, and regulatory communities, is recommended. Test validation acceptance is contingent on broad buy-in by disparate groups in the scientific community—academics, industry, and government. This is best achieved by early and frequent communication among parties and agreement on common goals. It is hoped that the creation of a validation infrastructure composed of the elements described in this report will facilitate scientific acceptance and utilization of alternative methodologies and speed implementation of replacement, reduction, and refinement alternatives in toxicity testing.