United States Voluntary Children's Chemical Evaluation Program (VCCEP) risk assessment for children exposed to benzene.

As part of the Voluntary Children's Chemical Evaluation Program (VCCEP) program, a risk assessment was performed to evaluate the risks to children from environmental benzene exposures. This paper summarizes this risk assessment. Risk was characterized using two distinct methods: USEPA's default type of risk assessment, which used the Reference Dose (RfD) and Cancer Slope Factor (CSF) to characterize non-cancer and cancer risks, as well as a Margin of Safety (MOS) approach that utilized a point of departure (POD). The exposures for most scenarios evaluated in this VCCEP risk assessment are lower than both the cancer and non-cancer PODs by several orders of magnitude, indicating a large MOS and corresponding low potential for toxicity at these exposures. The highest benzene exposures likely experienced by children, associated with the lowest MOS, are from cigarette smoke. In addition, the potential for age-related differences in the sensitivity towards benzene-induced toxicity was investigated. In general, this risk assessment does not indicate that children are likely to be at a elevated risk of AML or hematopoietic toxicity associated with environmental exposures to benzene.

A review and meta-analysis of prospective studies of red and processed meat intake and prostate cancer.

Over the past decade, several large epidemiologic investigations of meat intake and prostate cancer have been published. Therefore, a meta-analysis of prospective studies was conducted to estimate potential associations between red or processed meat intake and prostate cancer. Fifteen studies of red meat and 11 studies of processed meat were included in the analyses. High vs. low intake and dose-response analyses were conducted using random effects models to generate summary relative risk estimates (SRRE). No association between high vs. low red meat consumption (SRRE = 1.00, 95% CI: 0.96-1.05) or each 100 g increment of red meat (SRRE = 1.00, 95% CI: 0.95-1.05) and total prostate cancer was observed. Similarly, no association with red meat was observed for advanced prostate cancer (SRRE = 1.01, 95% CI: 0.94-1.09). A weakly elevated summary association between processed meat and total prostate cancer was found (SRRE = 1.05, 95% CI: 0.99-1.12), although heterogeneity was present, the association was attenuated in a sub-group analysis of studies that adjusted for multiple potential confounding factors, and publication bias likely affected the summary effect. In conclusion, the results of this meta-analysis are not supportive of an independent positive association between red or processed meat intake and prostate cancer.

A review and meta-analysis of red and processed meat consumption and breast cancer.

The relationship between meat consumption and breast cancer has been the focus of several epidemiological investigations, yet there has been no clear scientific consensus as to whether red or processed meat intake increases the risk of breast cancer. We conducted a comprehensive meta-analysis incorporating data from several recently published prospective studies of red or processed meat intake and breast cancer. In the meta-analysis utilising data from the Pooling Project publication (includes data from eight cohorts) combined with data from nine studies published between 2004 and 2009 and one study published in 1996, the fixed-effect summary relative risk estimate (SRRE) for red meat intake (high v. low) and breast cancer was 1·02 (95 % CI 0·98, 1·07; P value for heterogeneity = 0·001) and the random-effects SRRE was 1·07 (95 % CI 0·98, 1·17). The SRRE for each 100 g increment of red meat was 1·04 (95 % CI 1·00, 1·07), based on a fixed-effects model, and 1·12 (95 % CI 1·03, 1·23) based on a random-effects model. No association was observed for each 100 g increment of red meat among premenopausal women (SRRE 1·01; 95 % CI 0·92, 1·11) but a statistically significant SRRE of 1·22 (95 % CI 1·04, 1·44) was observed among postmenopausal women using a random-effects model. However, the association for postmenopausal women was attenuated and non-significant when using a fixed-effects model (SRRE 1·03; 95 % CI 0·98, 1·08). The fixed- and random-effect SRRE for high (v. low) processed meat intake and breast cancer were 1·00 (95 % CI 0·98, 1·01; P value for heterogeneity = 0·005) and 1·08 (95 % CI 1·01, 1·16), respectively. The fixed- and random-effect SRRE for each 30 g increment of processed meat were 1·03 (95 % CI 1·00, 1·06) and 1·06 (95 % CI 0·99, 1·14), respectively. Overall, weak positive summary associations were observed across all meta-analysis models, with the majority being non-statistically significant. Heterogeneity was evident in most analyses, summary associations were sensitive to the choice of analytical model (fixed v. random effects), and publication bias appeared to have produced slightly elevated summary associations. On the basis of this quantitative assessment, red meat and processed meat intake does not appear to be independently associated with increasing the risk of breast cancer, although further investigations of potential effect modifiers, such as analyses by hormone receptor status, may provide valuable insight to potential patterns of associations.

Potency factors for risk assessment at Libby, Montana.

We reanalyzed the Libby vermiculite miners' cohort assembled by Sullivan to estimate potency factors for lung cancer, mesothelioma, nonmalignant respiratory disease (NMRD), and all-cause mortality associated with exposure to Libby fibers. Our principal statistical tool for analyses of lung cancer, NMRD, and total mortality in the cohort was the time-dependent proportional hazards model. For mesothelioma, we used an extension of the Peto formula. For a cumulative exposure to Libby fiber of 100 f/mL-yr, our estimates of relative risk (RR) are as follows: lung cancer, RR = 1.12, 95% confidence interval (CI) =[1.06, 1.17]; NMRD, RR = 1.14, 95% CI =[1.09, 1.18]; total mortality, RR = 1.06, 95% CI =[1.04, 1.08]. These estimates were virtually identical when analyses were restricted to the subcohort of workers who were employed for at least one year. For mesothelioma, our estimate of potency is K(M) = 0.5 x 10(-8), 95% CI =[0.3 x 10(-8), 0.8 x 10(-8)]. Finally, we estimated the mortality ratios standardized against the U.S. population for lung cancer, NMRD, and total mortality and obtained estimates that were in good agreement with those reported by Sullivan. The estimated potency factors form the basis for a quantitative risk assessment at Libby.

Dermal absorption of arsenic from soils as measured in the rhesus monkey.

Regulatory agencies have relied on dermal absorption data for soluble forms of arsenic as the technical basis for specific absorption values that are used to calculate exposure to arsenic in weathered soil. These evaluations indicate that percutaneous absorption of arsenic from soil ranges from 3.2 to 4.5% of the dermally applied dose, based on studies of arsenic freshly mixed with soil. When this value is incorporated into risk assessments and combined with other assumptions about dermal exposures to soil, the conclusion is often that dermal exposure to arsenic from soil may contribute significantly to overall exposure to arsenic in soil. Prior characterization research has indicated that the solubility of arsenic in soil varies, depending on the provenance of the soil, the source of the arsenic, and the chemical interaction of arsenic with other minerals present within the soil matrix. Weathering produces forms of arsenic that are more tightly bound within the soil and less available for absorption. Our research expands on prior in vivo studies to provide insights into the potential for dermal absorption of arsenic from the more environmentally relevant substrate of soil. Specifically, two soils with very high concentrations of arsenic were evaluated under two levels of skin hydration. One soil, containing 1400 mg/kg arsenic, was collected adjacent to a pesticide production facility in New York. The other soil, containing 1230 mg/kg arsenic, was collected from a residential area with a history of application of arsenical pesticides. Although the results of this research are constrained by the small study size dictated by the selection of an animal research model using monkeys, the statistical power was optimized by using a "crossover" study design, wherein each animal could serve as its own comparison control. No other models (animal or in vitro) were deemed adequate for studying the dermal absorption of soil arsenic. Our results show dermal absorption of soluble arsenic in solution to be 4.8 +/- 5.5%, which is similar to results reported earlier for arsenic in solution (and used by regulatory agencies in recommendations regarding dermal absorption of arsenic). Conversely, absorption following application of arsenic in the soil matrices resulted in mean estimated arsenic absorption of 0.5% or less for all soils, and all individual estimates were less than 1%. More specifically, following application of arsenic-bearing soils to the abdomens of monkeys, urinary arsenic excretion could not be readily distinguished from background. This was true across all five soil-dosing trials, including application of the two dry soils and three trials with wet soil. These findings are consistent with our understanding of the environmental chemistry of arsenic, wherein arsenic can be present in soils in complexed mineral forms. This research addresses an important component involved in estimating the true contribution of percutaneous exposures to arsenic in soil relative to exposures via ingestion. Our findings suggest that dermal absorption of arsenic from soil is truly negligible, and that EPA's current default assumption of 3% dermal absorption of arsenic from soils results in significant overestimates of exposure.

State-of-the-science review: Does manganese exposure during welding pose a neurological risk?

Recent studies report that exposure to manganese (Mn), an essential component of welding electrodes and some steels, results in neurotoxicity and/or Parkinson's disease (PD) in welders. This "state-of-the-science" review presents a critical analysis of the published studies that were conducted on a variety of Mn-exposed occupational cohorts during the last 100 yr, as well as the regulatory history of Mn and welding fumes. Welders often perform a variety of different tasks with varying degrees of duration and ventilation, and hence, to accurately assess Mn exposures that occurred in occupational settings, some specific information on the historical work patterns of welders is desirable. This review includes a discussion of the types of exposures that occur during the welding process--for which limited information relating airborne Mn levels with specific welding activities exists--and the human health studies evaluating neurological effects in welders and other Mn-exposed cohorts, including miners, millers, and battery workers. Findings and implications of studies specifically conducted to evaluate neurobehavioral effects and the prevalence of PD in welders are also discussed. Existing exposure data indicate that, in general, Mn exposures in welders are less than those associated with the reports of clinical neurotoxicity (e.g., "manganism") in miners and smelter workers. It was also found that although manganism was observed in highly exposed workers, the scant exposure-response data available for welders do not support a conclusion that welding is associated with clinical neurotoxicity. The available data might support the development of reasonable "worst-case" exposure estimates for most welding activities, and suggest that exposure simulation studies would significantly refine such estimates. Our review ends with a discussion of the data gaps and areas for future research.

Do children have increased susceptibility for developing secondary acute myelogenous leukemia?

This study was undertaken to evaluate the effects of age on a child's susceptibility to developing leukemia following exposure to known leukemogenic agents. The clinical literature describing the risk of developing acute myelogenous leukemia (AML) following treatment with alkylating agents or topoisomerase reactive drugs (known leukemogens) was used as a basis for this investigation. Based on this preliminary assessment, the age of the child does not appear to be an independent variable for risk following treatment with either class of drug. Although the number of studies and cases was very small, the available scientific and medical literature does not support the hypothesis that children will necessarily have an altered susceptibility or increased risk of developing chemotherapy-induced AML.

Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort.

Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order back-extrapolations with half-lives of 7-9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDD's carcinogenic potency based on such data.

Meta-analysis of prospective studies of red meat consumption and colorectal cancer.

The relationship between red meat consumption and colorectal cancer (CRC) has been the subject of scientific debate. To estimate the summary association between red meat intake and CRC and to examine sources of heterogeneity, a meta-analysis of prospective studies was conducted. Thirty-four prospective studies of red meat and CRC were identified, of which 25 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose-response relationships were calculated. In the high versus low intake meta-analysis, the SRRE was 1.12 (95% CI: 1.04-1.21) with significant heterogeneity (P=0.014). Summary associations were modified by tumor site and sex. The SRREs for colon cancer and rectal cancer were 1.11 (95% CI: 1.03-1.19) and 1.19 (95% CI: 0.97-1.46), respectively. The SRREs among men and women were 1.21 (95% CI: 1.04-1.42) and 1.01 (95% CI: 0.87-1.17), respectively. The available epidemiologic data are not sufficient to support an independent and unequivocal positive association between red meat intake and CRC. This conclusion is based on summary associations that are weak in magnitude, heterogeneity across studies, inconsistent patterns of associations across the subgroup analyses, and the likely influence of confounding by other dietary and lifestyle factors.

Processed meat and colorectal cancer: a quantitative review of prospective epidemiologic studies.

A tremendous amount of scientific interest has been generated regarding processed meat consumption and cancer risk. Therefore, to estimate the association between processed meat intake and colorectal cancer (CRC), a meta-analysis of prospective studies was conducted. Twenty-eight prospective studies of processed meat and CRC were identified, of which 20 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose-response relationships were calculated. The SRRE for high (vs. low) processed meat intake and CRC was 1.16 [95% confidence interval (CI): 1.10-1.23] for all studies. Summary associations were modified considerably by sex; the SRRE for men was 1.23 (95% CI: 1.07-1.42) and the SRRE for women was 1.05 (95% CI: 0.94-1.16), based on nine and 13 studies, respectively. Sensitivity analyses did not indicate appreciable statistical variation by tumor site, processed meat groups, or study location. The SRRE for each 30-gram increment of processed meat and CRC was 1.10 (95% CI: 1.05-1.15) based on nine studies, and the SRRE for each incremental serving of processed meat per week was 1.03 (95% CI: 1.01-1.05) based on six studies. Overall, summary associations were weak in magnitude (i.e. most less than 1.20), processed meat definitions and analytical comparisons were highly variable across studies, and isolating the independent effects of processed meat intake is difficult, given the likely influence of confounding by other dietary and lifestyle factors. Therefore, the currently available epidemiologic evidence is not sufficient to support a clear and unequivocal independent positive association between processed meat consumption and CRC.

Partially hydrolyzed 100% whey protein infant formula and atopic dermatitis risk reduction: a systematic review of the literature.

The incidence of atopic dermatitis (AD) is increasing worldwide. Clinical studies have observed reduced risks of AD among infants fed with 100% whey partially hydrolyzed infant formula (PHF-W) compared with intact protein cow's milk formula. To evaluate this potential relationship more comprehensively, a systematic review of the literature was conducted. Studies (n = 18, representing 12 distinct study populations) that specified the protein source of the formula, evaluated healthy-term infants, compared the use of PHF-W with intact protein cow's milk formula, and reported results for AD were included. A critical assessment of the methodological quality of studies was conducted. In all studies, a reduced incidence of AD and/or atopic manifestations that included AD was observed. The cumulative incidence of AD was significantly lower among infants over at least 3 years of follow-up in the PHF-W group compared with the intact protein cow's milk group. Exclusive breastfeeding should be encouraged as the primary means to prevent atopic risk. However, when infants are not exclusively breastfed, PHF-W may be considered an effective measure to potentially reduce the risk of developing AD.

Quantitative assessment of red meat or processed meat consumption and kidney cancer.

OBJECTIVE: To conduct a quantitative assessment of red meat or processed meat consumption and kidney cancer. METHODS: We extracted data from 12 case-control studies, three cohort studies, and the Pooling Project of Diet and Cancer publication for which 13 international cohorts were evaluated. Random effects meta-analysis models were used to calculate summary relative risk estimates (SRRE) based on high vs. low intake values. Sensitivity and influence analyses were conducted, including assessments of heterogeneity. RESULTS: The SRRE for all studies that reported results for red meat (included variables labeled 'red meat' or single red meat items, such as beef, pork, or liver) was 1.12 (95% CI: 0.98-1.29; p-value for heterogeneity=0.015), and the SRRE using only data from prospective cohorts was 1.02 (95% CI: 0.91-1.15) with minimal heterogeneity (p=0.741). Similarly, in a meta-analysis of the five studies that simultaneously adjusted for smoking, BMI, and total energy intake, the SRRE for red meat was 1.02 (95% CI: 0.91-1.15). No significant association was observed in the meta-analysis of processed meat consumption (SRRE=1.07; 95% CI: 0.94-1.23), although a significant association was observed when only data from cohort studies were analyzed (SRRE=1.19; 95% CI: 1.03-1.37). CONCLUSIONS: Although many of the summary results were positive, all were weak in magnitude, most were not statistically significant, and associations were attenuated among studies that adjusted for key potential confounding factors. In summary, the findings of this meta-analysis are not supportive of an independent relation between red or processed meat intake and kidney cancer.

Meta-analysis of animal fat or animal protein intake and colorectal cancer.

BACKGROUND: In the recent World Cancer Research Fund/American Institute for Cancer Research report of diet and cancer, it was concluded that there is limited but suggestive evidence that animal fat intake increases the risk of colorectal cancer. OBJECTIVE: To clarify this potential relation, we conducted meta-analyses across a variety of subgroups, incorporating data from additional studies. DESIGN: Analyses of high compared with low animal fat intakes and categorical dose-response evaluations were conducted. Subgroup analyses, consisting of evaluations by study design, sex, and tumor site were also performed. RESULTS: Six prospective cohort studies with comprehensive dietary assessments, contributing 1070 cases of colorectal cancer and approximately 1.5 million person-years of follow-up, were identified. The summary relative risk estimate (SRRE) for these studies was 1.04 (95% CI: 0.83, 1.31; P for heterogeneity = 0.221) on the basis of high compared with low intakes. When data from case-control studies were combined with the cohort data, the resulting SRRE was 1.15 (95% CI: 0.93, 1.42) with increased variability (P for heterogeneity = 0.015). In our dose-response analysis of the cohort studies, no association between a 20-g/d increment in animal fat intake and colorectal cancer was observed (SRRE: 1.02; 95% CI: 0.95, 1.09). In a separate analysis of 3 prospective cohort studies that reported data for animal protein or meat protein, no significant association with colorectal cancer was observed (SRRE: 0.90; 95% CI: 0.70, 1.15). CONCLUSION: On the basis of the results of this quantitative assessment, the available epidemiologic evidence does not appear to support an independent association between animal fat intake or animal protein intake and colorectal cancer.

Data available for evaluating the risks and benefits of MTBE and ethanol as alternative fuel oxygenates.

The wide-scale use of methyl tertiary butyl ether (MTBE) in gasoline has resulted in substantial public controversy and action to ban or control its use due to perceived impacts on water quality. Because oxygenates are still required under federal law, considerable research has focused on ethanol as a substitute for MTBE. In this article, we summarize the currently available literature on the air and water quality risks and benefits of MTBE versus ethanol as alternative fuel oxygenates. We find that MTBE-fuel blends are likely to have substantial air quality benefits; ethanol-fuel blends appear to offer similar benefits, but these may be at least partially negated because of ethanol's propensity to increase emissions and ambient concentrations of some air contaminants. Releases of gasoline containing either MTBE or ethanol could have an impact on some drinking water sources, although the impacts associated with MTBE tend to relate to aesthetics (i.e., taste and odor), whereas the impacts associated with ethanol generally relate to health risk (i.e., greater exposure to gasoline constituents such as benzene). It is likely that these water quality impacts will be outweighed by the air quality benefits associated with MTBE and perhaps ethanol use, which affect a much larger population. A lack of data on environmental exposures and associated health impacts hinders the completion of a comprehensive quantitative risk-benefit analysis, and the available air and water quality data should be evaluated in a broader risk-management context, which considers the potential life-cycle impacts, costs, and feasibility associated with alternative fuel oxygenates.