Cancer Risk Estimation for Mixtures of Coal Tars

Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 × 10⁻⁴ (ppm coal tar in total diet) + 240 × 10⁻⁴ (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 × 10⁻⁴ (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 × 10⁻³ per μg per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 × 10⁻³ per μg per kg body weight per day listed in the U.S. EPA Integrated Risk Information System.     

Development of a Quantitative Microbial Risk Assessment for Human Salmonellosis Through Household Consumption of Fresh Minced Pork Meat in Belgium

A quantitative microbial risk assessment (QMRA) according to the Codex Alimentarius Principles is conducted to evaluate the risk of human salmonellosis through household consumption of fresh minced pork meat in Belgium. The quantitative exposure assessment is carried out by building a modular risk model, called the METZOON-model, which covers the pork production from farm to fork. In the METZOON-model, the food production pathway is split up in six consecutive modules: (1) primary production, (2) transport and lairage, (3) slaughterhouse, (4) postprocessing, (5) distribution and storage, and (6) preparation and consumption. All the modules are developed to resemble as closely as possible the Belgian situation, making use of the available national data. Several statistical refinements and improved modeling techniques are proposed. The model produces highly realistic results. The baseline predicted number of annual salmonellosis cases is 20,513 ( SD 9061.45). The risk is estimated higher for the susceptible population (estimate  4.713 × 10⁻⁵; SD 1.466 × 10⁻⁵  ) compared to the normal population  (estimate 7.704 × 10⁻⁶; SD 5.414 × 10⁻⁶)  and is mainly due to undercooking and to a smaller extent to cross-contamination in the kitchen via cook's hands.     

The BSE Risk of Processing Meat and Bone Meal in Nonruminant Feed: A Quantitative Assessment for the Netherlands

The total ban on use of meat and bone meal (MBM) in livestock feed has been very successful in reducing bovine spongiform encephalopathy (BSE) spread, but also implies a waste of high-quality proteins resulting in economic and ecological loss. Now that the BSE epidemic is fading out, a partial lifting of the MBM ban might be considered. The objective of this study was to assess the BSE risk for the Netherlands if MBM derived from animals fit for human consumption, i.e., category 3 MBM, would be used in nonruminant feed. A stochastic simulation model was constructed that calculates (1) the probability that infectivity of undetected BSE-infected cows ends up with calves and (2) the quantity of infectivity ( Q_inf ) consumed by calves in case of such an incident. Three pathways were considered via which infectivity can reach cattle: (1) cross-contamination in the feed mill, (2) cross-contamination on the primary farm, and (3) pasture contamination. Model calculations indicate that the overall probability that infectivity ends up with calves is 3.2%. In most such incidents the Q_inf is extremely small (median = 6.5 × 10⁻¹² ID₅₀; mean = 1.8 × 10⁻⁴ ID₅₀), corresponding to an average probability of 1.3 × 10⁻⁴ that an incident results in ≥1 new BSE infections. Cross-contamination in the feed mill is the most risky pathway. Combining model results with Dutch BSE prevalence estimates for the coming years, it can be concluded that the BSE risk of using category 3 MBM derived from Dutch cattle in nonruminant feed is very low.     

Risk Assessment for Aflatoxin: An Evaluation Based on the Multistage Model

Lifetime cancer potency of alfatoxin was assessed based on the Yeh et al. study from China in which both aflatoxin exposure and hepatitis B prevalence were measured. This study provides the best available information for estimating the carcinogenic risk posed by aflatoxin to the U.S. population. Cancer potency of aflatoxin was estimated using a biologically motivated risk assessment model. The best estimate of aflatoxin potency was 9 (mg/kg/day)⁻¹ for individuals negative for hepatitis B and 230 (mg/kg/day)⁻¹ for individuals positive for hepatitis B.     

Characterizing the Risk of Infection from Mycobacterium tuberculosis in Commercial Passenger Aircraft Using Quantitative Microbial Risk Assessment

Quantitative microbial risk assessment was used to predict the likelihood and spatial organization of Mycobacterium tuberculosis ( Mtb ) transmission in a commercial aircraft. Passenger exposure was predicted via a multizone Markov model in four scenarios: seated or moving infectious passengers and with or without filtration of recirculated cabin air. The traditional exponential ( k  = 1) and a new exponential ( k  = 0.0218) dose-response function were used to compute infection risk. Emission variability was included by Monte Carlo simulation. Infection risks were higher nearer and aft of the source; steady state airborne concentration levels were not attained. Expected incidence was low to moderate, with the central 95% ranging from 10⁻⁶ to 10⁻¹ per 169 passengers in the four scenarios. Emission rates used were low compared to measurements from active TB patients in wards, thus a "superspreader" emitting 44 quanta/h could produce 6.2 cases or more under these scenarios. Use of respiratory protection by the infectious source and/or susceptible passengers reduced infection incidence up to one order of magnitude.     

Risk Assessment of Nitrated Polycyclic Aromatic Hydrocarbons

Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) constitute a group of substances formed during incomplete combustion. Sources include diesel vehicles, heating, smoking, certain types of food-processing, and incomplete combustion in general. 2-Nitrofluorene (NF) represents a model substance for the nitro-PAHs. An attempt has been made to estimate the lifetime human cancer risk due to background exposure to nitro-PAHs by two different models. The first model is based on genotoxic lesions produced by gamma-irradiation and the second model is based on an earlier published mega study (24,000 animals) on the carcinogenicity of the major metabolite of NF. Both models agreed well-representing a yearly human cancer risk in the range of 0.15–49 × 10⁻⁶ for an urban citizen. The weaknesses and strengths of the models are discussed.     

On the Effect of Probability Distributions of Input Variables in Public Health Risk Assessment

A central part of probabilistic public health risk assessment is the selection of probability distributions for the uncertain input variables. In this paper, we apply the first-order reliability method (FORM)^(1–3) as a probabilistic tool to assess the effect of probability distributions of the input random variables on the probability that risk exceeds a threshold level (termed the probability of failure) and on the relevant probabilistic sensitivities. The analysis was applied to a case study given by Thompson et al. ⁽⁴⁾ on cancer risk caused by the ingestion of benzene contaminated soil. Normal, lognormal, and uniform distributions were used in the analysis. The results show that the selection of a probability distribution function for the uncertain variables in this case study had a moderate impact on the probability that values would fall above a given threshold risk when the threshold risk is at the 50th percentile of the original distribution given by Thompson et al. ⁽⁴⁾ The impact was much greater when the threshold risk level was at the 95th percentile. The impact on uncertainty sensitivity, however, showed a reversed trend, where the impact was more appreciable for the 50th percentile of the original distribution of risk given by Thompson et al. ⁴ than for the 95th percentile. Nevertheless, the choice of distribution shape did not alter the order of probabilistic sensitivity of the basic uncertain variables.     

An Evaluation of Alternative Safety Criteria for Nuclear Power Plants

Safety criteria for frequency of nuclear-reactor accidents and for reactor-induced risk to individuals and to society are evaluated on the basis of their comprehensiveness, clarity, recognition of uncertainty, practicability, defensibility, simplicity, and internal consistency. Many criteria were found to be comprehensive and practicable; few completely satisfied the other evaluation standards. A consensus inferred from the most favorably evaluated criteria would allow between 1.0time10^-4 and 1.0time10^-3 core melts per reactor year, between 1.0time10^-6 and 2.0time10^-5 fatalities per reactor year per individual, and a total exposure in the United States of between 1000 and 10,000 person rems per reactor year. This consensus is consistent with the criteria proposed in NUREG0880.     

Evacuation Risks: A Tentative Approach for Quantification

This study tries to assess the risk of deaths and injuries from motor vehicle accidents associated with an evacuation of population groups in case of nuclear plant accidents. The risk per person–km is evaluated using: (a) data from previous evacuation: information from Soufriere evacuation (Guadeloupe Island 1976) and Mississauga (1979), added to Hans and Sell's data: no road accident occurred for a sample of 1,500,000 persons; (b) national recording system for motor vehicle accident: the rates of 2.2 10 ^-8 deaths per person–km and 32 10^-8 injuries per person–km is calculated as an average. These last rates in France overestimate the number of casualties. A reasonable hypothesis is to assume that the probability of road accident occurrence follows a Poisson distribution, as these events are independent and unfrequent, as no accident was observed in a sample of 1,500,000 persons the probability is between 0 and an upper value of 0.24 10^-8 deaths per person-km and 3.29 10^-8 injuries per person–km. The average and maximum population involved within different radii around French and U.S. Nuclear power sites are taken as a sample size in order to study the total risk of deaths and injuries in the hypothesis of an evacuation being necessary to protect the populations.     

Connecticut's Dioxin Ambient Air Quality Standard

Connecticut is the first state in the country to have adopted an ambient air quality standard for dioxins at 1 pg/m³, 2,3,7,8-TCDD equivalents, as annual average. This paper describes the scientific basis and the methodology used by the State Department of Health Services (the risk assessment agency) in assisting the Department of Enviromental Protection (the risk management agency) to establish a health-based dioxin standard. This standard protects the public health from the aggregate effect of all sources of dioxin emissions in the vapor and particulate phases. The risk assessment methodology included: a limit on total daily dioxin exposure from all media and sources based on reproductive effects; a multimedia nonsource-specific exposure assessment; an apportionment by media of the health-based limit (including background dosing rate); an evaluation of inhalation bioavailability and cancer risk based on a calculation of a range of upperbound cancer risk estimates using different potency, bioavailability, and particle phase assumptions.     

Physiologically-Based Pharmacokinetic Model for Trichloroethylene Considering Enterohepatic Recirculation of Major Metabolites

Trichloroacetic acid (TCA) is major metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA in rats do not occur until approximately 12 hours following an oral dose of TRI. However, blood concentrations of TRI reach maximum within an hour and are nondetectable after 2 hours.⁽¹⁾ The results of study which examined the enterohepatic recirculation (EHC) of the principle TRI metabolited⁽²⁾ was used to develop physiologically-based pharmacokinetic model for TRI, which includes enterohepatic recirculation of its metabolites. The model quantitatively predicts the uptake, distribution and elimination of TRI, trichloroethanol, trichloroethanol-glucuronide, and TCA and includes production of metabolites through the enterohepatic recirculation pathway. Physiologic parameters used in the model were obtained from the literature.^(3.4) Parameters for TRI metabolism were taken from Fisher et al.⁽⁵⁾ Other kinetic parameters were found in the literature or estimated from experimental data.⁽²⁾ The model was calibrated to data from experiments of an earlier study where TRI was orally administered⁽²⁾ Verification of the model was conducted using data on the enterohepatic recirculation of TCEOH and TCA⁽²⁾ chloral hydrate data (infusion doses) from Merdink,⁽¹⁾ and TRI data from Templin(l) and Larson and Bull.⁽¹⁾     

Aggregating Disparate Epidemiological Evidence: Comparing Two Seminal EMF Reviews

Two seminal reviews ( IARC, 2002 ; CDHS, 2002 ) of possible health effects from power-frequency EMFs reached partly different conclusions from similar epidemiological evidence. These differences have an impact on precautionary policy. We examine the statistical aggregation of results from individual disparate studies. Without consistent exposure metrics, the advantage of meta-analysis to estimate magnitude of effect is lost. However, counting positive and statistically significant results yields important information. This is not a substitute for meta-analysis, but a fall-back when meaningful meta-analysis is not available. Representative results from 33 independent adult leukemia studies tabled by IARC yielded 23.5 positives ( p ≈ 0.01) and 9 significant-positives ( p  < 10⁻⁷). From 43 representative results from CDHS, there were 32 positive ( p  < 0.001) and 14 significant-positives ( p  < 10⁻¹²). There were no significant-negative results in either list. Results for adult brain cancer gave a similar, but less clear, message. Childhood leukemia EMF studies have been sufficiently comparable to allow selective pooled analysis, which was important in classifying carcinogenicity. Aggregating all the studies suggests that results for childhood leukemia are not stronger, numerically, than those for adult leukemia. CDHS did not note the number of significant-positives, but noted the meta-analytic summary and the number of positives, forming a view about the strength of these findings. IARC shows no evidence of considering the aggregation of results other than subjectively. It considered individual studies but this led to a tendency to fragment and dismiss evidence that is intrinsically highly significant. We make recommendations for future reviews.     

Assessing Health Risks Associated with DDT Residues in Soils in California: A Proposition 65 Case Study

Population growth in California has increased the pressure to convert agricultural land to commercial, industrial, or residential uses. In the ensuing property transactions, buyers and sellers must address the presence of toxic materials in soils such as pesticides, several of which are known to the State of California to cause cancer under Proposition 65. While this statute does not specifically address soil contaminants, the potential scope of its enforcement is sufficiently broad that owners of former agricultural properties may be obliged to provide warning of exposure to potential buyers, occupants, or construction workers about exposure to residues in soil from pesticide applications. However, Proposition 65 provides no guidance on how to assess exposures to chemicals in soil. The U.S. EPA Risk Assessment Guidance for Superfund (RAGS) provides a method for assessing soil-related exposure pathways that is consistent with the intent of Proposition 65. Using this approach, we have calculated the lifetime average concentrations of DDT in soil corresponding to the no-significant-risk level stipulated under Proposition 65 (1 × 10⁻⁵) for a hypothetical residential exposure scenario. The concentration of DDT in soil corresponding to a no-significant-risk ranges from 7.9-18.8 mg/kg, depending upon which exposure pathways are deemed to be complete for residential land use. It is argued that Proposition 65 forces the assessment and possible cleanup of such a situation through the threat of creating a health risk perception that could affect the market value of a property.     

Relative Contributions of Four Exposure Pathways to Influenza Infection Risk

The relative contribution of four influenza virus exposure pathways—(1) virus-contaminated hand contact with facial membranes, (2) inhalation of respirable cough particles, (3) inhalation of inspirable cough particles, and (4) spray of cough droplets onto facial membranes—must be quantified to determine the potential efficacy of nonpharmaceutical interventions of transmission. We used a mathematical model to estimate the relative contributions of the four pathways to infection risk in the context of a person attending a bed-ridden family member ill with influenza. Considering the uncertainties in the sparse human subject influenza dose-response data, we assumed alternative ratios of 3,200:1 and 1:1 for the infectivity of inhaled respirable virus to intranasally instilled virus. For the 3,200:1 ratio, pathways (1), (2), and (4) contribute substantially to influenza risk: at a virus saliva concentration of 10⁶ mL⁻¹, pathways (1), (2), (3), and (4) contribute, respectively, 31%, 17%, 0.52%, and 52% of the infection risk. With increasing virus concentrations, pathway (2) increases in importance, while pathway (4) decreases in importance. In contrast, for the 1:1 infectivity ratio, pathway (1) is the most important overall: at a virus saliva concentration of 10⁶ mL⁻¹, pathways (1), (2), (3), and (4) contribute, respectively, 93%, 0.037%, 3.3%, and 3.7% of the infection risk. With increasing virus concentrations, pathway (3) increases in importance, while pathway (4) decreases in importance. Given the sparse knowledge concerning influenza dose and infectivity via different exposure pathways, nonpharmaceutical interventions for influenza should simultaneously address potential exposure via hand contact to the face, inhalation, and droplet spray.     

Presenting Uncertainty in Health Risk Assessment: Initial Studies of Its Effects on Risk Perception and Trust

Some analysts suggest that discussing uncertainties in health risk assessments might reduce citizens'perceptions of risk and increase their respect for the risk-assessing agency. We tested this assumption with simulated news stories varying simple displays of uncertainty (e.g., a range of risk estimates, with and without graphics). Subjects from Eugene, Oregon, read one story each, and then answered a questionnaire. Three studies tested between 180 and 272 subjects each. Two focus groups obtained more detailed responses to these stories. The results suggested that (1) people are unfamiliar with uncertainty in risk assessments and in science; (2) people may recognize uncertainty when it is presented simply; (3) graphics may help people recognize uncertainty; (4) reactions to the environmental problems in the stories seemed affected less by presentation of uncertainty than by general risk attitudes and perceptions; (5) agency discussion of uncertainty in risk estimates may signal agency honesty and agency incompetence for some people; and (6) people seem to see lower risk estimates (10^-6, as opposed to 10^-3) as less credible. These findings, if confirmed, would have important implications for risk communication.     

Using Probabilistic Modeling to Evaluate Human Exposure to Organotin in Drinking Water Transported by Polyvinyl Chloride Pipe

The leaching of organotin (OT) heat stabilizers from polyvinyl chloride (PVC) pipes used in residential drinking water systems may affect the quality of drinking water. These OTs, principally mono- and di-substituted species of butyltins and methyltins, are a potential health concern because they belong to a broad class of compounds that may be immune, nervous, and reproductive system toxicants. In this article, we develop probability distributions of U.S. population exposures to mixtures of OTs encountered in drinking water transported by PVC pipes. We employed a family of mathematical models to estimate OT leaching rates from PVC pipe as a function of both surface area and time. We then integrated the distribution of estimated leaching rates into an exposure model that estimated the probability distribution of OT concentrations in tap waters and the resulting potential human OT exposures via tap water consumption. Our study results suggest that human OT exposures through tap water consumption are likely to be considerably lower than the World Health Organization (WHO) "safe" long-term concentration in drinking water (150 μg/L) for dibutyltin (DBT)—the most toxic of the OT considered in this article. The 90th percentile average daily dose (ADD) estimate of 0.034 ± 2.92 × 10⁻⁴μg/kg day is approximately 120 times lower than the WHO-based ADD for DBT (4.2 μg/kg day).     

The Possibility for "Natural" Generation of Chlorinated Organic Compounds

There is continuing concern for the exposure of persons to various chlorinated organics via the environment, for example, chlorinated disinfection byproducts in drinking water.⁽¹⁾ Some of these may be carcinogenic,⁽²⁾ although the evidence is far from strong.⁽³⁾ There is an accumulating body of evidence that one of the normal human immunological responses to foreign agents is the generation of hypochlorous acid. This evidence will be summarized. The possibility that this HOCl generated in vivo could result in the formation of organo-chlorine compounds does not appear to have been seriously considered. Based on best available information, the amount of such byproduct formation will be estimated.     

A Trichloroethylene Risk Assessment Using a Monte Carlo Analysis of Parameter Uncertainty in Conjunction with Physiologically-Based Pharmacokinetic Modeling

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10^-6 lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10^-6 risk.     

The Role of Environmental Accidental Risk Assessment in the Process of Granting Development Consent

Environmental impact assessment (EIA) is a procedure that must be followed for certain types of development before they are granted development consent. The procedure requires the developer to compile an environmental impact report (EIR) describing the likely significant effects of the project on the environment. A regulatory requirement in Slovenia is that an accidental risk assessment for a new installation should be a part of an EIR. The article shows how risk assessment (RA) related to accidental release of methylene diphenyl diisocyanate (MDI) or a polyvalent alcohol mixture from a new planned unit of a chemical factory in the Alpine region of Slovenia was performed in the framework of an EIA for the purpose of obtaining a construction permit. Two accidental scenarios were considered: (a) a spill of 20 m³ of MDI or polyvalent alcohol mixture into the river Soča (the river runs close to the chemical factory) and (b) a fire in the warehouse storing the raw material, where emission of toxic gases HCN, NO_x, and CO is expected during combustion of MDI. One of the most important results of this case is the agreement among the developer, the competent authority, and a consultant in the field of EIA and RA to positively conclude the licensing process despite the absence of formal (regulatory) limit values for risk. It has been approved that transparent, reasonably uncertain, and semi-quantitative environmental risk assessment is an inevitable component of an EIA, and an essential factor in informed, licensing-related decision making.     

Bounding Estimates for Critical Events When Directly Disposing Highly Enriched Spent Nuclear Fuel in Unsaturated Tuff

This paper examines the possibility of criticality in a nuclear waste repository. The estimated probabilities are rough bounds and do not entirely dismiss the possibility of a critical condition; however, they do point to the difficulty of creating conditions under which a critical mass could be assembled (i.e., corrosion of containers, separation of neutron absorbers from the fissile material, and collapse or precipitation of the fissile material). In addition, should a criticality occur in or near a container, the bounding consequence calculations showed that fissions from one critical event are quite small (<˜10²⁰ fissions, if similar to aqueous and metal accidents and experiments). Furthermore, a reasonable upper bound of total critical events of 10²⁸ fissions corresponds to only 0.1% of the number of fissions represented by the spent nuclear fuel inventory in a repository containing 70,000 metric tons of heavy metal (MTHM) (the expected size for the proposed repository at Yucca Mountain, Nevada).