Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment.

There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.

Health survey of workers exposed to mixed solvent and ergonomic hazards in footwear and equipment factory workers in Thailand.

A cross-sectional health study was performed at four footwear and one equipment factory in Thailand to evaluate the prevalence of chemical- and ergonomic-related symptoms in Thai factory workers and to investigate associations between these symptoms and exposures to organic solvents, isocyanates and ergonomic risks. A 10-page health questionnaire was administered to 1784 workers across the four footwear and equipment factories. A total of 1675 questionnaires were returned, yielding a 94% response rate. The questionnaires asked about age, gender, use of chemicals, use of personal protective equipment and health outcomes. Without exception, the percentages of workers reporting symptoms after being hired were higher than those reporting symptoms before being hired for all the factories. The highest symptom percentages were related to ergonomic stressors. Multiple logistic regression was used to calculate adjusted prevalence odds ratios and 95% confidence intervals. This study showed that adverse health effects experienced by footwear and equipment factory workers are associated with occupational exposures to chemicals (volatile organic solvents and water-based adhesives) and ergonomic hazards.

Modeling cholinesterase activity for human dietary risk assessment of carbamate insecticides.

This article demonstrates statistical models to quantify the interaction between a carbamate insecticide and acetylcholinesterase. Carbamates are a class of chemicals that inhibit the activity of acetylcholinesterase in humans, an enzyme involved in the regulation of the neurotransmitter acetylcholine. Following exposure to a carbamate insecticide, we specifically address (1) if acetylcholinesterase activity recovers to its level of preexposure activity; (2) the level of inhibition of acetylcholinesterase activity; (3) the recovery time of acetylcholinesterase activity to its preexposure level for a typical individual; and (4) the upper percentiles of the recovery time of acetylcholinesterase activity across individuals. A nonlinear mixed-effects model is fitted to data from a repeated measures experiment conducted with human volunteers randomly assigned to a control and four dose groups. Repeated measurements were taken prior to exposure and at 1, 2, 4, 6, 8, and 21 hours after exposure to the carbamate aldicarb. It was found that full recovery did occur. Inhibition at 1 hour was estimated with maximum inhibition most likely occurring prior to 1-hour postexposure. In addition, recovery was rapid even for sensitive individuals. Given this information, the potential effect from exposure to a carbamate consumed in the diet during a day can be quantitatively assessed.

A survey of airborne and skin exposures to chemicals in footwear and equipment factories in Thailand.

This research reports on a pilot industrial hygiene study that was performed at four footwear factories and two equipment factories in Thailand. Workers in these factories were exposed through inhalation and dermal contact to a large number of organic vapors from solvents and cements that were hand applied. In addition, these workers were exposed to highly toxic isocyanates primarily through the dermal route. A total of 286 personal air samples were obtained at the four footwear factories using organic vapor monitors; individual job tasks were monitored using a real-time MIRAN Spectrometer. A total of 64 surface, tool, or hand samples were monitored for isocyanates using surface contamination detectors. Real-time measurements were also obtained for organic vapors in two equipment factories. From 8% to 21% of the workers sampled in each footwear factory were overexposed to mixtures of chemicals from solvents and cements. Up to 100% of the workers performing specific job tasks were overexposed to mixtures of chemicals. From 39% to 69% of the surface samples were positive for unreacted isocyanates. Many of the real-time measurements obtained in the equipment factories exceeded occupational exposure limits. Personal protective equipment and engineering controls were inadequate in all of the factories.

Evaluating uncertainty to strengthen epidemiologic data for use in human health risk assessments.

BACKGROUND: There is a recognized need to improve the application of epidemiologic data in human health risk assessment especially for understanding and characterizing risks from environmental and occupational exposures. Although there is uncertainty associated with the results of most epidemiologic studies, techniques exist to characterize uncertainty that can be applied to improve weight-of-evidence evaluations and risk characterization efforts. METHODS: This report derives from a Health and Environmental Sciences Institute (HESI) workshop held in Research Triangle Park, North Carolina, to discuss the utility of using epidemiologic data in risk assessments, including the use of advanced analytic methods to address sources of uncertainty. Epidemiologists, toxicologists, and risk assessors from academia, government, and industry convened to discuss uncertainty, exposure assessment, and application of analytic methods to address these challenges. SYNTHESIS: Several recommendations emerged to help improve the utility of epidemiologic data in risk assessment. For example, improved characterization of uncertainty is needed to allow risk assessors to quantitatively assess potential sources of bias. Data are needed to facilitate this quantitative analysis, and interdisciplinary approaches will help ensure that sufficient information is collected for a thorough uncertainty evaluation. Advanced analytic methods and tools such as directed acyclic graphs (DAGs) and Bayesian statistical techniques can provide important insights and support interpretation of epidemiologic data. CONCLUSIONS: The discussions and recommendations from this workshop demonstrate that there are practical steps that the scientific community can adopt to strengthen epidemiologic data for decision making.

Within-day drinking water consumption patterns: results from a drinking water consumption survey.

Data currently available on drinking water intakes do not support dietary exposure estimates for contaminants that have acute effects lasting less than 24 h. Realistic exposure estimates for these types of contaminants in drinking water require detailed information on amounts and time of consumption for each drinking occasion during a day. A nationwide water consumption survey was conducted to address how often, when, and how much water is consumed at specific times during the day. The survey was conducted in two waves, to represent two seasons, and the survey instrument consisted of 7-day water consumption diaries. Data on total daily amounts consumed, number of drinking occasions per day, amounts consumed per drinking occasion, and intervals between drinking occasions show larger between-subjects variation than within-subject variation. Statistically significant associations were also observed between drinking water consumption patterns and participants' ages and sex and geographical regions in which these participants live. The number of drinking occasions on a given day varied from 0 to 19, with the majority of respondents reporting 6 or less drinking occasions per day. The average interval between drinking occasions varied from 1 to 17 h, with 57% of the person-days reporting average intervals at least 3 h apart. The mean amount consumed per drinking occasion showed little association with the number of drinking occasions and fluctuated between 8 and 10 oz. To our knowledge, this survey is the only source of information on within-day patterns (i.e., when and how much) of drinking water consumption for a nationally representative sample of the US population. The detailed water consumption data from this survey can be used to support less than 24-h dietary exposure estimates for contaminants in drinking water.

Derivation of single layer clothing penetration factors from the pesticide handlers exposure database.

Quantitative characterization of the penetration of chemical residues through various types and configurations of clothing is an important underpinning of mitigation strategies to reduce dermal exposure to occupational cohorts. The objective of the evaluation presented herein is the development of pesticide clothing penetration (or conversely protection) factors for single layer clothing (i.e., long-sleeved shirt, long pants; gloves are not included) based on dermal exposure monitoring data (passive dosimetry) included in the Environmental Protection Agency's Pesticide Handlers Exposure Database (PHED). The analysis of penetration per replicate was conducted by comparison of the inside and outside (total deposition), expressed as mug/cm(2), for each replicate pair of dermal dosimeters. Clothing penetration was investigated as a function of job classification, dosimetry sampling method, body part, application method, and type of formulation. Grand mean single layer clothing penetration values for patch (n=2029) and whole-body (n=100) dosimeter samples from PHED were 12.12 (SE=0.33; SD=15.02) and 8.21 (SE=1.01; SD=10.14) percent, respectively. Linear regression was used to evaluate clothing penetration as a function of outer dosimeter loading. The regression analysis supports the hypothesis that single layer clothing penetration increases with decreasing outer dosimeter loading.

Plutonium-related work and cause-specific mortality at the United States Department of Energy Hanford Site.

BACKGROUND: Health effects of working with plutonium remain unclear. Plutonium workers at the United States Department of Energy (US-DOE) Hanford Site in Washington State, USA were evaluated for increased risks of cancer and non-cancer mortality. METHODS: Periods of employment in jobs with routine or non-routine potential for plutonium exposure were identified for 26,389 workers hired between 1944 and 1978. Life table regression was used to examine associations of length of employment in plutonium jobs with confirmed plutonium deposition and with cause specific mortality through 1994. RESULTS: Incidence of confirmed internal plutonium deposition in all plutonium workers was 15.4 times greater than in other Hanford jobs. Plutonium workers had low death rates compared to other workers, particularly for cancer causes. Mortality for several causes was positively associated with length of employment in routine plutonium jobs, especially for employment at older ages. At ages 50 and above, death rates for non-external causes of death, all cancers, cancers of tissues where plutonium deposits, and lung cancer, increased 2.0 +/- 1.1%, 2.6 +/- 2.0%, 4.9 +/- 3.3%, and 7.1 +/- 3.4% (+/-SE) per year of employment in routine plutonium jobs, respectively. CONCLUSIONS: Workers employed in jobs with routine potential for plutonium exposure have low mortality rates compared to other Hanford workers even with adjustment for demographic, socioeconomic, and employment factors. This may be due, in part, to medical screening. Associations between duration of employment in jobs with routine potential for plutonium exposure and mortality may indicate occupational exposure effects.