Evaluating the Relationship Between Variance in Enzyme Expression and Toxicant Concentration in Health Risk Assessment

The replacement of default uncertainty factors with those based on chemical-specific data is a topic of interest to a growing number of government-based organizations and those in affiliated professional societies. The division of the uncertainty factors for animal-to-human extrapolation and human interindividual variance (UF_A and UF_H, respectively) into their pharmacodynamic (PD) and pharmacokinetic (PK) components invites additional and specific considerations. Where data are available, or substantiated PK models have been developed, the animal-to-human chemical-specific differences have been quantified and utilized to replace the PK component of the uncertainty factor. The increasing degree to which the genome is being characterized has stimulated additional interest in describing the impact of genetic polymorphisms on susceptibility. Frequently, proteins for which the genes are being evaluated are the group of xenobiotic metabolizing enzymes. In-depth understanding of the genetic polymorphisms of genes coding for Aldehyde dehydrogenase, glucuronyl transferase and cytochrome P450 enzyme forms has been combined with information on the bioactivation or detoxication of environmental contaminants. The preliminary conclusion of some of these considerations is that alterations in enzyme content or enzyme activity result in a de facto alteration of risk. While this may be true of the “all-or-none” genetic alterations, the impact of more subtle changes in enzyme content and/or activity are more difficult to predict. The hepatotoxicity of trichloroethylene (TCE) is dependent upon an initial, cytochrome P450 2E1 (CYP2E1)-mediated oxidative step. Variance of CYP2E1 content of human liver has been characterized from a bank of tissues from human organ donors and combined with data describing the in vitro Michaelis-Menten kinetic parameters in order to extrapolate the metabolic capacity (and variance thereof) from in vitro to in vivo and assess its impact on PK through incorporation in a physiologically based pharmacokinetic (PBPK) model. This presentation summarizes that work, and demonstrates and discusses why extremes of CYP2E1-mediated metabolic capacity in adult humans has virtually no impact on the PK metric most closely related to hepatotoxic injury from TCE exposure.     

Exposure Monitoring and Health Risk Assessment of 1-Bromopropane as a Cleaning Solvent in the Workplace

This study was conducted to estimate the health risk to workers exposed to 1-bromopropane (1-BP) used as a cleaning solvent in their workplaces. Fifty samples from 10 workplaces that use 1-BP as a cleaning solvent were obtained to assess 1-BP concentrations. An exposure assessment revealed central tendency exposure (CTE) and reasonable maximum exposure (RME) levels of 82.1 and 214.8 mg/m³, respectively. For risk characterization, the 1-BP exposure concentrations for reproductive and developmental toxicities were calculated as 2.8 and 8.5 mg/m³, respectively, and compared with the reference concentrations in the workplace. The CTE and RME hazard quotients (HQ) were, respectively, 29.4 and 77.0 for reproductive toxicity and 9.6 and 25.2 for developmental toxicity. The results of our 1-BP risk assessment indicated that the CTE-HQs for both categories were higher than the acceptable risk value of 1, indicating that 1-BP may be considered as harmful to workers.     

Framework for Human Health Risk Assessment

The U.S. Environmental Protection Agency has recognized the need to develop a framework for human health risk assessment that puts a perspective on the approaches in practice throughout the Agency. In response, the Agency's Risk Assessment Forum has begun the long-term process of developing a framework for human health risk assessment. The framework will be a communication piece that will lay out the scientific basis, principles, and policy choices underlying past and current risk assessment approaches and will provide recommendations for integrating/harmonizing risk assessment methodologies for all human health endpoints.     

Framework for Human Health Risk Assessment

The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the USEPA. The U.S. Government has the right to retain a nonexclusive royalty-free license in and to any copyright covering this article. The U.S. Environmental Protection Agency has recognized the need to develop a framework for human health risk assessment that puts a perspective on the approaches in practice throughout the Agency. In response, the USEPA's Risk Assessment Forum has begun the process of developing a framework for human health risk assessment. This paper provides some additional background to the previous review of the framework efforts and notes the Agency's extramural efforts to begin the process of integrating and harmonizing risk assessment approaches for all human health endpoints.     

Monitoring for the Management of Disease Risk in Animal Translocation Programmes

We conducted an observational study to determine the prevalence of Entamoeba spp., in samples collected in a waste water treatment plant that provides water for agricultural irrigation. Samples were collected weekly over a period of 10 weeks at representative contamination stages from within the treatment plant. Protozoan identification was performed via light microscopy and culture. PCR amplification of small subunit rRNA gene sequences of E. histolytica/dispar/moshkovskii was performed in culture positive samples. Light microscopy revealed the presence of Entamoeba spp., in 70% (14/20) of the raw waste water samples and in 80% (8/10) of the treated water samples. PCR amplification after culture at both 24 and 37°C revealed that 100% (29/29) of the raw waste water samples and 78.6% (11/14) of the treated waste water were positive for E. moshkovskii. We report the first isolation of E. moshkovskii in Colombia, confirmed by PCR. Recent reports of E. moshkovskii pathogenic potential suggest this finding could constitute a public health risk for people exposed to this water.     

Monitoring for the Management of Disease Risk in Animal Translocation Programmes

Monitoring is best viewed as a component of some larger programme focused on science or conservation. The value of monitoring is determined by the extent to which it informs the parent process. Animal translocation programmes are typically designed to augment or establish viable animal populations without changing the local community in any detrimental way. Such programmes seek to minimize disease risk to local wild animals, to translocated animals, and in some cases to humans. Disease monitoring can inform translocation decisions by (1) providing information for state-dependent decisions, (2) assessing progress towards programme objectives, and (3) permitting learning in order to make better decisions in the future. Here we discuss specific decisions that can be informed by both pre-release and post-release disease monitoring programmes. We specify state variables and vital rates needed to inform these decisions. We then discuss monitoring data and analytic methods that can be used to estimate these state variables and vital rates. Our discussion is necessarily general, but hopefully provides a basis for tailoring disease monitoring approaches to specific translocation programmes.     

Framework for the Integration of Health and Ecological Risk Assessment

The World Health Organization's International Programme on Chemical Safety (IPCS), the Organization for Economic Cooperation and Development (OECD), and the U.S. Environmental Protection Agency have developed a collaborative partnership to foster integration of assessment approaches for human health and ecological risks. This paper presents the framework developed by that group. Integration provides coherent expressions of assessment results, incorporates the interdependence of humans and the environment, uses sentinel organisms, and improves the efficiency and quality of assessments relative to independent human health and ecological risk assessments. The paper describes how integration can occur within each component of risk assessment, and communicates the benefits of integration at each point. The goal of this effort is to promote the use of this internationally accepted guidance as a basis for harmonization of risk assessment.     

Human Health Risk Assessment: Required Reading

Over the past 30 years, risk assessment has developed into a scientific discipline. It is critical that the next generation of risk assessors understand the history of our field, and recognize the numerous successes and failures that have taken place. This short Perspective identifies and describes specific books, monographs, and reports that are required reading for any nascent risk assessor.     

Biomarkers as Predictors in Health and Ecological Risk Assessment

Biomarkers are measurable biological parameters that change in response to xenobiotic exposure and other environmental or physiological stressors, and can be indices of toxicant exposure or effects. If the biomarkers are sufficiently specific and well characterized, they can have great utility in the risk assessment process by providing an indication of the degree of exposure of humans or animals in natural populations to a specific xenobiotic or class of xenobiotics. Most biomarkers are effective as indices of exposure, but adequate information is rarely available on the appropriate dose-response curves to have well-described biomarkers of effect that can be widely applicable to additional populations. Specific examples of acetylcholinest-erase inhibition following exposure to organophosphorus insecticides are cited from experiments in both mammals (rats) and fish. These experiments have indicated that the degree of inhibition can be readily influenced by endogenous (e.g., age) and exogenous (e.g., chemical exposures) factors, and that the degree of inhibition is not readily correlated with toxicological effects. Caution is urged, therefore, in an attempt to utilize biomarkers in the risk assessment process until more complete documentation is available on the specificity, sensitivity, and time course of changes, and on the impact of multiple exposures or the time of exposures.     

Health Risk Assessment of Lead in the Republic of Korea

The purpose of this study was to estimate the daily exposure to lead due to food ingestion, air inhalation, and soil ingestion in the Republic of Korea's general population, and to evaluate the level of risk associated with the current lead exposure level using the proportional daily dose (3–4 μg/kg body weight/day) corresponding to the Provisional Tolerable Weekly Intake (PTWI) suggested by the Joint FAO/WHO Expert Committee on Food Additives as the toxicological tolerance level. The estimation of the daily exposure to lead via three pathways including food, soil ingestion and air inhalation was conducted as a chronic exposure assessment. For the lead exposure assessment through dietary intake, 1,389 lead residue data for 45 commodities investigated by the Korea Food and Drug Administration during the period 1995–2000 were utilized (KFDA 1996, 1997, 1998). Six hundred seventy-two air monitoring data from 7 major cities during the period 1993–2000 and 4,500 soil residue data at 1,500 sites during the period 1999–2001 were considered for the lead exposure assessment involving air inhalation and soil ingestion, respectively. The total daily exposure to lead was estimated by combining dietary intake, inhaled amount and soil intake corresponding to the typical activity of the general population, which was treated as a group of adults with a body weight of 60 kg. For risk characterization, the daily exposure to lead was compared with the toxicological tolerance level. The level of risk due to lead exposure was calculated using the hazard ratio (HR). The dietary intake of lead was 9.71 × 10_?4 mg/kg/day and the total daily exposure level, including air inhalation and soil ingestion, was 9.97 × 10_?4 mg/kg/day. The exposure contributions of foods, air and soil induced from the percentage of each media to the total daily exposure were 97.4%, 2.1% and 0.5%, respectively. Of the different commodity groups, the highest contribution to the total exposure came from grain, which represented 47.7% of the total. Additional exposure to lead occurs in certain population groups due to the use of tobacco, alcoholic beverages, and the intake of other foods, all factors not considered in this study. Through the comparison of the daily exposure to lead with the tolerance level based on the PTWI, the hazard ratio was estimated as being 0.25–0.33. This value implies that no increase in blood lead level is to be expected in the general population at the current lead exposure levels.     

Environmental Monitoring of Heavy Metal Status and Human Health Risk Assessment in the Agricultural Soils of the Jinxi River Area,China

Soil contamination with heavy metals is one of the main environmental concerns in China, mainly owing to rapid industrialization and mining activities in certain areas. The current study aimed at monitoring the levels of heavy metals in soils of the industrial areas along the Jinxi River and surrounding Lake Qingshan. In addition, a health risk assessment for humans in contact with these soils was also conducted. The results revealed that the soils of the studied areas were contaminated with Cr, Cu, As, Se, Cd, Pb, and Zn and that the industrial activities were the main source of soil contamination therein. Furthermore, soils of the sites adjacent to Lin’an city exhibited higher levels of heavy metals than the upstream and Lake Qingshan sites. Most of the studied heavy metals tended to concentrate in the fine soil fractions (PM100, PM10, and PM2.5). Calculation of the hazard index (HI) revealed that humans, especially children, have potential health risks. Moreover, As was found to contribute to more magnitude of cancer risks. Thus, we concluded that the unmanaged development negatively affects the Chinese environment and human health. Furthermore, fine fractions of soil particles should be considered for risk assessment.     

Public Health Risk Assessment Linked to Climatic and Ecological Change

Disturbances of climatic and ecological systems can present risks to human health, which are becoming more evident from health studies linked to climate variability, landuse change and global climate change. Waterborne disease agents, such as Giardia cysts and Cryposporidium oocysts have been positively correlated with rainfall. El Niño-related extreme weather conditions can have a significant impact on vector- and water-borne diseases. The linkages between weather, terrestrial ecology and human health have been discovered for some diseases, such as rodent-borne hantavirus. Marine ecology also plays a role in determining human health risks, such as from cholera, and other enteric pathogens. Deforestation and ensuing changes in landuse, human settlement, commercial development, road construction, and water control systems singly, and in combination have been accompanied by increases in or emergence of diseases like malaria and schistosomiasis in some regions of the world. Long-term climate change may increase the frequency of heat waves and potentially air pollution episodes, increase the number of extreme weather events, cause coastal flooding and salination of fresh water aquifers, and displace coastal settlements. Ultimately, a two-pronged approach (empirical and modeling studies) is required to better understand these linkages between climato-logical and ecological change as determinants of disease.     

Impact Assessment of an Independent Agency for Animal Health in England

The applicability of a stochastic model was explored to assess the impact of a new independent agency for animal health in England in terms of the cost of animal disease outbreaks. The new agency was proposed to take responsibility for animal disease management in England. The stochastic model estimates the likelihood that the proposed new agency would face animal disease outbreaks of major and minor magnitude; and how many outbreaks of each magnitude, within its first 30 years of operation. Large variability in the potential total cost of the new agency was attributable to the possibility of an outbreak of an unknown major disease, although Bluetongue, Foot and Mouth Disease, and Avian Influenza were also influential. The results show that if the new agency reduces disease costs by even 0.5%, this could benefit society by an estimated £21 million per year. The stochastic approach offers a method for dealing with uncertainties in any continuing deliberations regarding the proposed new agency, resulting in a potential annual gain of £73 million ranging to an annual loss of £144 million.     

Quantitative Assessment of the Association Between MS Gene Polymorphism and Colorectal Cancer Risk

Accumulating genetic association studies have investigated the risk of colorectal cancer (CRC) in relation to MS gene polymorphism with uncertain conclusions. In the current study, we sought to assess the association between MS gene and CRC. We performed an updated meta-analysis including 18 case-control studies with a total of 10, 303 CRC patients and 15, 389 CRC-free controls to estimate the strength of the association using odds ratios with the corresponding 95 % confidence intervals. Overall, no CRC risk associated with the genotypes of MS gene polymorphism was indicated in our meta-analysis. Similarly, the stratified analysis according to ethnicity and control source did not show any evident association either. The results of our updated meta-analysis suggest that MS gene polymorphism may not serve as a biomarker for the CRC risk. Future large-scale and well-designed studies are required to clarify the association identified in the present meta-analysis.     

Safety Risk Assessment and Improvement in a Food Production Process

The food industry is under pressure to improve food safety, implement efficient risk management, and control quality “from farm to fork.” During processing of raw materials into packaged consumable products, food may be influenced by biological and chemical pollution and other various environmental factors. Risk assessment of a food production process was studied in this work. The novelty of this work lies in analyzing the development laws of food safety risk in serial and parallel modes, and developing a heuristic algorithm of polynomial time to minimize safety risks in food production with a constant budget. This algorithm was validated by a numerical example of peanut milk production. The primary procedures in peanut milk production were found and the advice on investment allocation was given to improve production.     

A Human Health Risk Assessment of Pharmaceuticals in the Aquatic Environment

Analyses were conducted on four pharmaceutical compounds, representing different therapeutic classes, to evaluate the presence and potential adverse human health effects of trace levels of these substances in aqueous environmental media. Acetylsalicylic acid, clofibrate, cyclophosphamide, and indomethacin have been detected in aqueous environmental media including sewage treatment plant effluent, surface water, drinking water, and groundwater. An extensive literature search and chemical-specific risk assessments were performed to assess the potential human health significance of each compound's individual presence in environmental media. Safe water quality limits were estimated for each pharmaceutical by following the USEPA Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health and were compared to the concentrations found in the environment. The calculation of the provisional ambient water quality criteria involved estimation of human exposure to contaminated water, including intake via bioaccumulation in fish, and calculation of cancer risk and non-cancer hazard indices. Parameters detailing the toxicological and pharmacological nature, exposure assessment, and environmental fate and transport of each pharmaceutical were also considered. The overall conclusion was that based on available data, no appreciable risk to humans exists, as the detected concentrations of each of these pharmaceutical compounds found in aqueous media were far below the derived safe limits     

Benzene Exposure at Gasoline Stations: Health Risk Assessment

This study aimed to assess the health risk of benzene exposure among gasoline stations workers. There were 98 workers from each zone of gasoline station in Muang Khon Kaen,Thailand. The benzene concentrations were monitored via personal air sampling and analyzed with a gas chromatography flame-ionization detector (GC-FID). Information about adverse symptoms were obtained by an interview questionnaire. Levels of health risk were calculated from the likelihood level of exposure and the adverse symptoms level, which were summarized in a risk matrix. Most workers had experienced adverse symptoms related to benzene toxicity (68.4%). The health risk of benzene exposure was higher than an acceptable level in 15.3% of workers and in a similarly proportion of fueling workers and cashiers. Moreover, the proportion of risk group was found highest in urban zone (18%) and the risk scores had a significant difference across all zones. This study showed that over 15% of workers were under health risk conditions on benzene exposure and over 60% of workers had experienced adverse symptoms related to benzene toxicity. Therefore, findings suggest the need of the health surveillance program and safety training for workers to increase awareness of benzene exposure.