Environmental Protection Agency Risk Assessment Research Articles

Health risk assessment of exposure to benzene, toluene, ethylbenzene and xylenes in a vehicle manufacturing industry in Iran

IntroductionConsidering the adverse carcinogenic and non-carcinogenic health effects of Volatile Organic Compounds (VOC) and specially Benzene, Toluene, Ethylbenzene and Xylenes (BTEX) which are widely used in vehicle manufacturing industry, it is clear that monitoring and control of occupational exposure to these substances is of utmost significance. More often than not the studies on occupational exposure to VOCs in vehicle manufacturing industry—specifically BTEX—have been carried out exclusively in paint shop units. The purpose of this study was to assess occupational BTEX exposure & health risk in different units of a vehicle manufacturing industry.Material and methodsFoam injection unit (FIU), gluing unit (GU), repair shop unit (RSU), molding unit (MU) as well as paint shop units (PSU) were selected for this study. Sampling and analysis were conducted based on National Institute for Occupational Safety and Health (NIOSH) 1501 guidelines by utilizing MSA personal sampling pumps set to 0.2 l/m and Gas Chromatography equipped with Flame Ionization Detector (GC-FID). Risk characterization and assessment was performed using Environmental Protection Agency Risk Assessment Information System (EPA RAIS).Results and conclusionThe results revealed that the concentration of benzene in gluing and paint shop units was above occupational exposure limits. Carcinogenic risk levels in 8 out of 10 units registered in the 1E-2 to 1E-4 range, and only two units registered a risk level below EPA’s acceptable risk level (10–6). The highest risk levels were measured in gluing, paint shop and repair shop units. Furthermore, the total non-carcinogenic hazard quotient was measured higher than 1 in 8 out of 10 studied units. Considering the abundance and wide use of VOCs -most notably BTEX- and the adverse carcinogenic and non-carcinogenic health effects of these compounds, it is advised to: change the type of paint used in paint shops, improve the existing ventilation systems, develop new and more efficient ventilation systems and conduct consistent training.

Comprehensive interventions to reduce occupational hazards among medical staff in the pathology department of five primary hospitals

ObjectiveTo explore comprehensive interventions to reduce occupational hazards among medical staff in the pathology department of five primary hospitals.MethodsThe indoor air quality in the pathology department of five primary hospitals and the health status of staff were investigated and analyzed. Formaldehyde and benzene concentrations in the technical and diagnostic rooms of the pathology departments were analyzed before and after comprehensive interventions. The Environmental Protection Agency risk assessment paradigm was used to assess the health risks from occupational exposure to benzene and formaldehyde. Consequently, considering the local environment, targeted comprehensive intervention measures were developed, including optimizing management, raising awareness, updating equipment, and replacing reagents.ResultsEye discomfort was higher among technicians in the pathology department than among clinical medical staff (P < 0.05). Before comprehensive interventions, formaldehyde concentrations were higher in the technical room than in the diagnostic room at the five primary hospitals (P < 0.05). However, compared to before interventions, formaldehyde and benzene concentrations in both rooms were significantly lower after comprehensive interventions. Furthermore, although medium risks of occupational exposure to benzene and formaldehyde remained in both rooms before and after comprehensive interventions, the risk values before interventions were higher than after comprehensive interventions. The staff of the technical rooms showed higher risk values that those of the diagnostic rooms before and after comprehensive interventions. Similarly, although hazard quotient (HQ) values for occupational exposure to benzene and formaldehyde were < 1 in both the technical and diagnostic rooms before and after comprehensive interventions, with lower noncarcinogenic risks, the values were higher before than after comprehensive interventions. Moreover, staff in the technical room had higher HQ values before and after comprehensive interventions than those in the diagnostic room. The use of environmentally friendly reagents for the preparation of frozen sections was effective.ConclusionComprehensive interventions significantly reduced occupational hazards among staff at the pathology department of five primary hospitals, which is of great practical significance to protect the health of staff.

Health risks of pest control and disinfection workers after the COVID-19 outbreak in South Korea

The exposure patterns of pest control and disinfection workers have changed after the coronavirus disease 2019 (COVID-19) outbreak, but the health risks of chemical exposure have not been assessed. We identified these workers' chemical exposure patterns and risks before and after the COVID-19 outbreak. We used data conducted between 2018 (pre-pandemic) and 2021 (post-pandemic) from three-year cross-sectional surveys on pest control and disinfection workers. Inhalation and dermal exposure concentrations were estimated using equations based on a biocidal product risk assessment model from the Korean National Institute of Environmental Research. The non-carcinogenic and carcinogenic risks of chemicals were calculated using the United States Environmental Protection Agency risk assessment model. We found that the annual work frequency (50th percentile) of foggers using disinfectants increased the most among all the work types, from 140 uses/year to 176 uses/year after the COVID-19 outbreak. Moreover, all chemicals' non-carcinogenic and carcinogenic risks increased regardless of exposure routes. In the worst scenario (95th percentile), the margin of exposure for citric acid, benzethonium chloride, benzyl-C12-16-alkyldimethyl chlorides, and sodium chlorite of inhalation exposure, and isopropyl alcohol and benzyl-C12-16-alkyldimethyl chlorides of dermal exposure were acceptable (>100) before the COVID-19 outbreak but became unacceptable (<100) after the COVID-19 outbreak. Carcinogenic risks of dichlorvos from inhalation and dermal exposure were above acceptable levels (>10−6) before and after the COVID-19 outbreak but comparatively high after the COVID-19 outbreak. Additionally, significantly more workers experienced health symptoms after the COVID-19 outbreak (p<0.05), with the most common being muscle lethargy (31%), skin/face stinging (28.7%), and breath shortness/neck pain (24.1%).

Levels, Sources, and Health Damage of Dust in Grain Transportation and Storage: A Case Study of Chinese Grain Storage Companies

A large amount of mixed dust exists in grain, which can easily stimulate the respiratory system and cause diseases. This study explored contamination levels and health effects of this grain dust. A total of 616 dust samples from different stages and types of grain were collected in China—in Hefei (Anhui), Shenzhen (Guangdong), Chengdu (Sichuan), Changchun (Jilin), and Shunyi (Beijing)—and analyzed using the filter membrane method and a laser particle size analyzer. A probabilistic risk assessment model was developed to explore the health effects of grain dust on workers in the grain storage industry based on the United States Environmental Protection Agency risk assessment model and the Monte Carlo simulation method. Sensitivity analysis methods were used to analyze the various exposure parameters and influencing factors that affect the health risk assessment results. This assessment model was applied to translate health risks into disability-adjusted life years (DALY). The results revealed that the concentration of dust ranged from 25 to 70 mg/m3, which followed normal distribution and the proportion of dust with a particle size of less than 10 μm exceeded 10%. Workers in the transporting stage were exposed to the largest health risk, which followed a lognormal distribution. The average health risks for workers in the entering and exiting zones were slightly below 2.5 × 10−5. The sensitivity analysis indicated that average time, exposure duration, inhalation rate, and dust concentration made great contributions to dust health risk. Workers in the grain storage and transportation stage had the health damage, and the average DALY exceeded 0.4 years.

Potentially harmful heavy metal contamination in Babolrood river: evaluation for risk assessment in the Mazandaran province, Iran

ABSTRACT Rivers,as the kind of freshwater resources throughout the world, play a key role in the lives of living things. Heavy metal contamination of river water is primarily attributed to human activities, and there is anincreasing need to conduct risk assessments to characterise the nature and magnitude ofrisks to humans and ecological receptors from these contaminants.The PG990 nuclear absorption spectrophotometer measured concentrations of heavy metals. Trace metals (Cd, Pb, Ni, Zn) in Babolrood river from the Babol region of North Iran were analysed to assess pollution using the Hazard Quotients (HQ), Hazard Index (HI) and the Incremental Lifetime Cancer Risk (ILCR).The Environmental Protection Agency (EPA) model was applied to calculate human health risk (HHR). Heavy metal concentration varied considerably Cd (0.004 to 89.287 µg/L), Ni (0.89–49.78 µg/L), Pb (3.4–181.75 µg/L) and Ni (0.0–243.3 µg/L). The oral Hazard quotients (HQ) values for Pb were ranged from 1.04–7.83 µg/L, therefore indicated in all sampled stations HQ values above 1 for children group. In contrast, the oral and dermal HQ values for both groups were less than 1 for Zn and Ni in all sampling stations. The Hazard Index (HI) values demonstrate that total HI values were above 1 for children group in water samples of all stations. Generally, total HI values for children were much higher than that of adults among Babolrood River. The Excess Lifetime Cancer Risk (ELCR) values for Cd and Pb in all sample stations for children were higher than the EPA risk assessment guideline limit (10−6-10−4).

The effect of the Environmental Protection Agency maximum contaminant level on arsenic exposure in the USA from 2003 to 2014: an analysis of the National Health and Nutrition Examination Survey (NHANES)

BackgroundThe current US Environmental Protection Agency (EPA) maximum contaminant level (MCL) for arsenic in public water systems (10 µg/L) took effect in 2006. Arsenic is not federally regulated in private wells. The impact of the 2006 MCL on arsenic exposure in the US, as confirmed through biomarkers, is presently unknown. We evaluated national trends in water arsenic exposure in the US, hypothesizing that urinary arsenic levels would decrease over time among participants using public water systems but not among those using well water. We further estimated the expected number of avoided lung, bladder, and skin cancer cases.MethodsWe evaluated 14,127 participants in the National Health and Nutrition Examination Survey (NHANES) 2003–2014 with urinary dimethylarsinate (DMA) and total arsenic available. To isolate water exposure, we expanded a residual-based method to remove tobacco and dietary contributions of arsenic. We applied EPA risk assessment approaches to estimate the expected annual number of avoided cancer cases comparing arsenic exposure in 2013–2014 vs. 2003–2004.FindingsAmong public water users, fully adjusted geometric means (GMs) of DMA decreased from 3.01 µg/L in 2003–2004 to 2.49 µg/L in 2013–2014 (17% reduction; 95% confidence interval 10%, 24%; p-trend<0.01); no change was observed among well water users (p-trend= 0.35). Assuming these estimated exposure reductions will remain similar across a lifetime, we estimate a reduction of 200 to 900 lung and bladder cancer cases per year depending on the approach used.InterpretationThe decline in urinary arsenic among public water but not private well users in NHANES 2003–2014 indicates that the implementation of the current MCL has reduced arsenic exposure in the US population. Our study supports prior work showing that well water users are inadequately protected against drinking water arsenic, and confirms the critical role of federal drinking water regulations in reducing toxic exposures and protecting human health.FundingThis work was supported by the National Institute of Environmental Health Sciences (1R01ES025216, R01ES021367, 5P30ES009089 and P42ES010349). A. E. Nigra was supported by 5T32ES007322.

Human health risk assessment of multiple contaminants due to consumption of animal-based foods available in the markets of Shanghai, China.

To assess the health risks due to food consumption, the human daily intake and uptake of organochlorine pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and toxic trace elements (mercury, chromium, cadmium, lead, and arsenic) were estimated based on the animal-based foods collected from markets in Shanghai, China. The estimated daily intake and uptake considering the contaminant bioaccessibility via single food consumption were 9.4-399 and 4.2-282ng/kg body weight/day for adults, and 10.8-458 and 4.8-323ng/kg body weight/day for children, respectively. These values were 0.2-104 and 0.05-58.1, and 0.2-119 and 0.06-66.6ng/kg body weight/day via multiple food consumption for adults and children, respectively. According to the United States Environmental Protection Agency risk assessment method, the non-cancer and cancer health risks posed by the contaminants were estimated using the hazard quotient and the lifetime cancer risk method, respectively. The results showed that the combined hazard quotient values for multiple contaminants via single or multiple food consumption were below 1, suggesting that the residents in Shanghai would not experience a significant non-cancer health risk. Among the contaminants investigated, the potential non-cancer risk of methylmercury was highest. However, the combined cancer risk posed by multiple contaminants in most foods exceeded the accepted risk level of 10(-6), and inorganic arsenic was the main contributor. The risks caused by polybrominated diphenyl ethers for cancer and non-cancer effects were negligible. The cancer risk of inorganic arsenic is a matter of concern in animal-based foods from Shanghai markets.

Interstate Comparison of Soil Remediation Standards among Six Mid-Atlantic States, USA

To address and help mitigate potential public health and ecological impacts associated with contaminated soil, most state environmental agencies have promulgated cleanup standards or action level criteria that are based broadly on US Environmental Protection Agency risk assessment methodologies. These standards or criteria often are assembled into easy-to-use look-up tables that allow responsible parties (RPs) to determine quickly the extent of remediation that could be required simply by comparing site investigation data to the listed cleanup goal or standard. This paper compares and contrasts soil remediation standards and criteria for 20 common soil pollutants taken from state environmental agency look-up tables for five Middle Atlantic States: New York, Connecticut, New Jersey, Delaware, Pennsylvania, and Maryland. We examine the differences between numeric remedial goals for these pollutants and propose a relative rank for each state based on the overall degree of soil cleanup standard or criterion stringency. In order to identify and rank the stringency of the residential cleanup goals or standards published by the six Mid-Atlantic States, a three-step process was used that included compiling in one data set, the numerical (mg/kg), residential or unrestricted use look-up values published by state for each of the 20 contaminants; organizing and grouping those values in numerical sequence into one of three categories ranging from lowest (Most Restrictive) to highest (Least Restrictive); and then ranking each state by the number of first place finishes in each stringency category: Most Restrictive, Moderately Restrictive, and Least Restrictive. The socioeconomic consequences of these ranks were examined relative to their effects on gross state product, unemployment, and health.

Derivation of Health-Based Screening Levels for Evaluating Indoor Surface Contamination

Abstract This paper describes the development of U.S. Army Public Health Command (Provisional) Technical Guide 312, Health Risk Assessment Methods and Screening Levels for Evaluating Office Worker Exposures to Contaminants on Indoor Surfaces Using Surface Wipe Data. Surface sampling of indoor surfaces may be performed to determine whether a building is safe for re-entry following an event (for example, fire, pesticide application) or change in building use (for example, laboratory to administrative office). Surface wipe sampling results may be used to assess either the degree of contamination before cleanup or to determine whether post-abatement (also post-remediation, post-clearance) actions were effective. The U.S. Army Public Health Command (Provisional) Environmental Health Risk Assessment Program has conducted risk assessments based on surface wipe sampling data and, over time, has evolved the methodology into a technical guide. The technical guide addresses the need to develop an approach to characterize potential health risk to exposed populations using surface wipe sampling results and to provide surface wipe screening levels to facilitate initial assessments. The methodology provides a means to estimate office worker exposures from inhalation of resuspended particles, dermal contact, and incidental ingestion exposure routes. Potential chemical health risks from aggregated intakes are evaluated using conventional U.S. Environmental Protection Agency risk assessment methods.

Perspective on the use of LNT for Radiation Protection and Risk Assessment by the U.S. Environmental Protection Agency

The U.S. Environmental Protection Agency (EPA) bases its risk assessments, regulatory limits, and nonregulatory guidelines for population exposures to low level ionizing radiation on the linear no-threshold (LNT) hypothesis, which assumes that the risk of cancer due to a low dose exposure is proportional to dose, with no threshold. The use of LNT for radiation protection purposes has been repeatedly endorsed by authoritative scientific advisory bodies, including the National Academy of Sciences' BEIR Committees, whose recommendations form a primary basis of EPA's risk assessment methodology. Although recent radiobiological findings indicate novel damage and repair processes at low doses, LNT is supported by data from both epidemiology and radiobiology. Given the current state of the science, the consensus positions of key scientific and governmental bodies, as well as the conservatism and calculational convenience of the LNT assumption, it is unlikely that EPA will modify this approach in the near future.

Pesticides: Carbofuran under Review

In the 31 July 2008 Federal Register, the Environmental Protection Agency (EPA) published a proposal to revoke all food “tolerances” of the insecticide carbofuran—residue allowances that are allowed to appear on food—on both domestic and imported produce, based on excessive risks to children and wildlife. If approved, this reversal of a July 2006 decision to allow carbofuran tolerances on imported coffee, bananas, sugarcane, and rice would sidestep the need for all-out cancellation of the pesticide’s registration. Carbofuran (trade name Furadan) is a restricted-use pesticide registered in the United States since 1969. The compound causes overstimulation of the nervous system by inhibiting acetyl-cholinesterase. Symptoms of overexposure in humans include headache, weakness, abdominal cramping, nausea, blurred vision, convulsion, tremor, and coma. Carbofuran is highly toxic to birds, fish, and bees. The proposal to revoke tolerances was necessary to protect children, says agency spokesperson Dale Kemery, because “studies have consistently shown that juvenile rats are more sensitive to carbo-furan than adult rats.” Based on EPA risk assessments, children up to age 5 also “experience the highest levels of dietary risk because they tend to eat larger amounts of food per their body weight than do teenagers or adults and because their systems for detoxifying contaminants are still developing.” That assessment was overly conservative, argues John Cummings, regulatory manager for North America at the Agricultural Products Group of FMC Corporation, the sole U.S. manufacturer of carbo-furan. Cummings says the EPA’s risk calculation includes the use of three safety factors, whereas FMC argues that the toxicologic data support a value of 100× for the combination of these factors but not the 400× asserted by the EPA. The three safety factors include a 10× interspecies factor used to extrapolate from animal data to humans, a 10× intraspecies factor used to account for possible variations between individuals, and a 4× uncertainty factor that is permissible under the Food Quality Protection Act. The EPA is only reacting to the law, Kemery says: “We are required by section 408 of the Federal Food Drug and Cosmetic Act to take into account the potential for children to be more sensitive in establishing safe levels on food—for example, by including additional safety factors in our calculations.” The American Bird Conservancy, which has fought for several years to have carbo-furan banned, points out that as far back as 1980 EPA scientists had estimated that over a million birds were killed each year by the granular formulation of carbofuran, the registration for which was cancelled in 1994. Beyond the tolerance revocation, the EPA embarked years ago on an effort to ban all U.S. sales of carbofuran by cancelling its registration altogether on the basis of dietary, occupational, and environmental considerations. This larger move has gotten support from several environmental groups. Alternatively, several U.S. grower groups and the U.S. Department of Agriculture have asked the EPA to consider alternatives to cancellation, claiming carbofuran is economically important to U.S. agriculture. About 1 million pounds are used annually on fruit and vegetable crops including corn, cotton, potatoes, sunflowers, and tobacco. If, following the 29 September 2008 deadline for comments on the proposed action, the EPA issues a final tolerance revocation, FMC could request a hearing. If the revocation becomes law, it would become illegal to sell domestic or imported food bearing any residue of carbo-furan; enforcement would be the responsibility of the Food and Drug Administration.

Potential New Approaches for Children's Inhalation Risk Assessment

The U.S. Environmental Protection Agency (EPA) practice of risk assessment is moving toward more thoroughly considering children's unique susceptibilities and exposure potential. Childhood is assessed as a sequence of life stages that reflects the fact that as humans develop, windows of susceptibility may appear that lead to enhanced sensitivity to exposure of environmental agents, while changes in behavior and physiology may increase exposure and dose. The U.S. EPA developed guidance in the past few years that addresses some aspects of increased susceptibility and exposure and dose. However, when it comes to considering inhalation exposure, dose, and risk, current U.S. EPA practice does not explicitly address children. The purpose here is to begin studying the adequacy of practice for children's health and to explore possible next steps in developing new methods to more accurately assess life-stage-specific differences. The existing guidelines and policies used to address potentially unique susceptibilities of children for inhaled environmental chemicals were considered, as well as what may be learned from examples of approaches that have been applied by state agencies (such as the California Environmental Protection Agency) or in the literature, to incorporate potentially unique susceptibilities and exposures to children. Finally, there is a discussion of possible approaches for considering inhalation exposure and susceptibility in U.S. EPA risk assessments.

If cumulative risk assessment is the answer, what is the question?

Cumulative risk refers to the combined threats from exposure via all relevant routes to multiple stressors including biological, chemical, physical, and psychosocial entities. Cumulative risk assessment is a tool for organizing and analyzing information to examine, characterize, and possibly quantify the combined adverse effects on human health or ecologic resources from multiple environmental stressors. The U.S. Environmental Protection Agency (EPA) has initiated a long-term effort to develop future guidelines for cumulative risk assessment, including publication in 2003 of a framework that describes important features of the process and discusses theoretical issues, technical matters, and key definitions. The framework divides the process of cumulative risk assessment into three interrelated phases: a) planning, scoping, and problem formulation; b) analysis; and c) interpretation and risk characterization. It also discusses the additional complexities introduced by attempts to analyze cumulative risks from multiple stressors and describes some of the theoretical approaches that can be used. The development of guidelines for cumulative risk assessment is an essential element in the transition of the U.S. EPA risk assessment methodology from a narrow focus on a single stressor, end point, source, pathway, and exposure route to a broader, more holistic approach involving analysis of combined effects of cumulative exposure to multiple stressors via all relevant sources, pathways, and routes.

An examination of the Environmental Protection Agency risk assessment principles and practices: a brief commentary on section 4.1.3 of the EPA March 2004 Staff Paper

The US Environmental Protection Agency (EPA) recently issued a Staff Paper that articulates current risk assessment practices. In section 4.1.3, EPA states, "... effects that appear to be adaptive, non-adverse, or beneficial may not be mentioned." This statement may be perceived as precluding risk assessments based on non-default risk models, including the hormetic--or biphasic--dose-response model. This commentary examines several potential interpretations of this statement and the anticipated impact of ignoring hormesis, if present, in light of necessary conservatism for protecting human and environmental health, and the potential for employing alternative risk assessment approaches.

The case for integrating low dose, beneficial responses into US EPA risk assessments

When conducting risk assessments, the US Environmental Protection Agency (EPA) does not currently consider the beneficial effects from exposure to concentrations of agents below the no observed adverse effect level (NOAEL). If such benefits were observed, and if the beneficial and toxicological mechanisms of action were identical, this would probably be represented as a 'j-shaped' hormetic dose-response curve. If such data are available, they should be considered when assigning uncertainty factors for safe exposure calculations. However, when such data are not readily available, as is likely the case when the mechanism of action of the benefit differs from that of toxicity, current US EPA methods appear adequate.

The perils and promise of modern risk assessment: the example of trichloroethylene.

This article summarizes some of the major scientific shortcomings identified by reviewers of the draft "Trichloroethylene Health Risk Assessment: Synthesis and Characterization" (TCE HRA) in the context of current US Environmental Protection Agency risk assessment guidance and the Data Quality Act guidelines. Our purpose is not to further criticize the draft HRA but to highlight specific areas for improvement and suggest specific ameliorative actions that we believe would improve the scientific credibility (quality) of the final document. This exercise is expected to be applicable beyond the specific case of TCE, because the draft HRA surely exemplifies many of the new challenges being posed to risk assessment in general by the ever-increasing sophistication of modern science.

Assessment of Human Health and Ecological Risks Posed by the Uses of Steel-Industry Slags in the Environment

Steel-industry slag, a co-product of iron and steel production, is produced and sold for use in a wide range of applications. A comprehensive study of the potential human health risks associated with the environmental applications (e.g., fill, roadbase, landscaping) of iron- and steel-making slag was performed using characterization data for 73 samples of slag collected from blast furnaces, basic oxygen furnaces, and electric arc furnaces. Characterization data were compared to regulatory health-based “screening” benchmarks to determine constituents of interest. Antimony, beryllium, cadmium, trivalent and hexavalent chromium, manganese, thallium, and vanadium were measured above screening levels and were assessed in an application-specific exposure assessment using standard U.S. Environmental Protection Agency risk assessment methods. A stochastic analysis was conducted to evaluate the variability and uncertainty in the inhalation exposure and risk estimates, and the oral bioaccessibility of certain metals in the slag was quantified. The risk assessment found no significant hazards to human health as a result of the environmental applications of steel-industry slag. However, site-specific ecological risk assessment may be required for slag applications in and around small water bodies with limited dilution volume, because high pH and aluminum were found to leach at levels that may be harmful to aquatic life

US EPA's acute reference exposure methodology for acute inhalation exposures

The US Environmental Protection Agency (EPA) National Center for Environmental Assessment is engaged in the development of a methodology for Agency use to perform risk assessments for non-cancer effects due to acute inhalation exposures. The methodology will provide general guidance for deriving chemical-specific acute exposure benchmarks called acute reference exposures (AREs). Chemical-specific AREs are analogous to reference concentrations (RfCs) for chronic non-cancer effects and will be incorporated in chemical-specific files in the US EPA's Integrated Risk Information System (IRIS) as they are developed and reviewed. AREs will have wide applicability in assessing the potential health risks of accidental and routine acute releases of chemicals to the environment. The proposed methodology for ARE development provides a framework for choosing an optimal derivation approach, depending on the type of data available, from the no-observed-adverse-effect level (NOAEL), benchmark concentration (BMC), or categorical regression approaches. Uncertainty factors are applied to the point of departure, determined by one of the recommended approaches, to derive the ARE. Due to the capability to use more exposure–response information than the NOAEL approach allows, exposure–response analyses such as BMC and categorical regression are favored as methods to develop the point of departure when the available database will support such analyses. The NOAEL approach is suitable when the data are insufficient to support exposure–response modeling. Applications of the proposed ARE methodology are illustrated by the derivation of example AREs for hydrogen sulfide and hexachlorocyclopentadiene, which showcase the categorical regression and NOAEL approaches, respectively. In addition, a recent review of the proposed ARE methodology by the US EPA Risk Assessment Forum is discussed.

Dose–response implications of the University of Alabama study of lymphohematopoietic cancer among workers exposed to 1,3-butadiene and styrene in the synthetic rubber industry

New quantitative cancer risk estimates for exposure to 1,3-butadiene are presented. These estimates are based on the most recent human epidemiologic data developed by Drs Delzell and Macaluso and their colleagues at the University of Alabama at Birmingham. The implications of Poisson regression analyses of the relative rate for leukemia are explored using their updated dose estimates and lymphohematopoietic cancer data. The Poisson regression model in these analyses has the same form as in the U.S. Environmental Protection Agency (EPA)'s draft risk assessment of 1,3-butadiene [U.S. Environmental Protection Agency, Health Risk Assessment of 1,3-Butadiene — External Review Draft, National Center for Environmental Assessment, Office of Research and Development, 63 Fed. Reg. 7167 (February 12, 1998) Publication NCEA-W-0267, Washington, 1998]. Consistent with the proposed cancer risk assessment guidelines of the EPA and the EPA's draft risk assessment, the exploration includes the maximum likelihood estimate of the ‘effective concentration’ (EC 01) corresponding to an extra risk of leukemia of 0.01 (1%) from a lifetime continuous exposure to 1,3-butadiene based on a linear dose–response model and the cumulative 1,3-butadiene dose metric (ppm-years). The incorporation of the most recent exposure estimates results in a 2.5-fold decrease in the estimates of leukemia risks computed by EPA. In addition, three changes proposed by the American Chemistry Council (formerly the Chemical Manufacturers Association) to the EPA's Science Advisory Board (SAB) for EPA's draft risk assessment of 1,3-butadiene are incorporated into the calculation. This results in approximately an additional fivefold decrease in the risk estimates of leukemia. The leukemia cancer risk estimates in the EPA's draft risk assessment of 1,3-butadiene decrease by approximately a factor of 13-fold when the updated epidemiologic data and the alternative numbers proposed by industry to the SAB are both incorporated. Specifically, the maximum likelihood estimate of the EC 01 increases from EPA's 1.2 ppm to 2.8 ppm on the basis of the updated epidemiologic data and increases further to 15.1 ppm when the CMA's proposed changes are also incorporated.

A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines.

The current United States Environmental Protection Agency (EPA) classification of di(2-ethylhexyl)phthalate (DEHP) as a B2 "probable human" carcinogen is based on outdated information. New toxicology data and a considerable amount of new mechanistic evidence were used to reconsider the cancer classification of DEHP under EPA's proposed new cancer risk assessment guidelines. The total weight-of-evidence clearly indicates that DEHP is not genotoxic. In vivo administration of DEHP to rats and mice results in peroxisome proliferation in the liver, and there is strong evidence and scientific consensus that, in rodents, peroxisome proliferation is directly associated with the onset of liver cancer. Peroxisome proliferation is a transcription-mediated process that involves activation by the peroxisome proliferator of a nuclear receptor in rodent liver called the peroxisome proliferator-activated receptor (PPARalpha). The critical role of PPARalpha in peroxisomal proliferation and carcinogenicity in mice is clearly established by the lack of either response in mice genetically modified to remove the PPARalpha. Several mechanisms have been proposed to explain how, in rodents, peroxisome proliferation can lead to the formation of hepatocellular tumors. The general consensus of scientific opinion is that PPARalpha-induced mitogenesis and cell proliferation are probably the major mechanisms responsible for peroxisome proliferator-induced hepatocarcinogenesis in rodents. Oxidative stress appears to play a significant role in this increased cell proliferation. It triggers the release of TNFalpha by Kupffer cells, which in turn acts as a potent mitogen in hepatocytes. Rats and mice are uniquely responsive to the morphological, biochemical, and chronic carcinogenic effects of peroxisome proliferators, while guinea pigs, dogs, nonhuman primates, and humans are essentially nonresponsive or refractory; Syrian hamsters exhibit intermediate responsiveness. These differences are explained, in part, by marked interspecies variations in the expression of PPARalpha, with levels of expression in humans being only 1-10% of the levels found in rat and mouse liver. Recent studies of DEHP clearly indicate a nonlinear dose-response curve that strongly suggests the existence of a dose threshold below which tumors in rodents are not induced. Thus, the hepatocarcinogenic effects of DEHP in rodents result directly from the receptor-mediated, threshold-based mechanism of peroxisome proliferation, a well-understood process associated uniquely with rodents. Since humans are quite refractory to peroxisomal proliferation, even following exposure to potent proliferators such as hypolipidemic drugs, it is concluded that the hepatocarcinogenic response of rodents to DEHP is not relevant to human cancer risk at any anticipated exposure level. DEHP should be classified an unlikely human carcinogen with a margin of exposure (MOE) approach to risk assessment. The most appropriate and conservative point of reference for assessing MOEs should be 20 mg/kg/day, which is the mouse NOEL for peroxisome proliferation and increased liver weight. Exposure of the general human population to DEHP is approximately 30 microg/kg body wt/day, the major source being from residues in food. Higher exposures occur occupationally [up to about 700 microg/kg body wt/day (mainly by inhalation) based on current workplace standards] and through use of certain medical devices [e.g., up to 457 microg/kg body wt/day for hemodialysis patients (intravenous)], although these have little relevance because the routes of exposure bypass critical activation enzymes in the gastrointestinal tract.