Prioritizing Chemicals and Data Requirements for Screening-Level Exposure and Risk Assessment

Background: Scientists and regulatory agencies strive to identify chemicals that may cause harmful effects to humans and the environment; however, prioritization is challenging because of the large number of chemicals requiring evaluation and limited data and resources.Objectives: We aimed to prioritize chemicals for exposure and exposure potential and obtain a quantitative perspective on research needs to better address uncertainty in screening assessments.Methods: We used a multimedia mass balance model to prioritize > 12,000 organic chemicals using four far-field human exposure metrics. The propagation of variance (uncertainty) in key chemical information used as model input for calculating exposure metrics was quantified.Results: Modeled human concentrations and intake rates span approximately 17 and 15 orders of magnitude, respectively. Estimates of exposure potential using human concentrations and a unit emission rate span approximately 13 orders of magnitude, and intake fractions span 7 orders of magnitude. The actual chemical emission rate contributes the greatest variance (uncertainty) in exposure estimates. The human biotransformation half-life is the second greatest source of uncertainty in estimated concentrations. In general, biotransformation and biodegradation half-lives are greater sources of uncertainty in modeled exposure and exposure potential than chemical partition coefficients.Conclusions: Mechanistic exposure modeling is suitable for screening and prioritizing large numbers of chemicals. By including uncertainty analysis and uncertainty in chemical information in the exposure estimates, these methods can help identify and address the important sources of uncertainty in human exposure and risk assessment in a systematic manner.     

A strategy for delineating risks due to exposure to neurotoxic chemicals.

A method for delineating the risks due to exposure to neurotoxic chemicals based upon the linkage of four national computer-based registers is described. The four registers are: the Danish Product Register database, PROBAS; Register of air pollution measurements in Danish workplaces, ATABAS; Register of notified occupational diseases; and Register of work force. Based on the information from the four registers, risk profiles for neurotoxic chemicals in 69 industrial groups were generated. The risk profiles describe the number of neurotoxic chemicals, their potency, the number of exposure measurements exceeding the occupational exposure limit (OEL), and the total and relative number of diseases caused by the chemicals in each group. Based on this linkage, twelve industries are noted to be potentially at high risk due to exposure to neurotoxic chemicals; therein, 18 chemicals are identified as "risk chemicals," primarily used in 8 main groups of products. The goal of the evaluation is to develop a tool for priority setting of preventive measures. The evaluation may also serve as a tool for assessing improvements and selecting areas for further epidemiological studies.     

Occupational risk and toxicology evaluations of industrial water conditioning

This study addresses the chemical and toxicological questionsdue to the wide use of chemical treatment programmes for industrialcooling water. First, natural problems encountered in coolingtower systems were presented and grouped into three categories:(i) scaling; (ii) corrosion and (iii) biofouling. Chemical solutionsadopted in industrial plants were outlined for each one in orderto minimize damage and catagorized as shut-down, productionloss, heat transfer reduction, upsets, etc. Above all, the purposeof the work was to identify the most dangerous chemicals normallyused, which mean sources of chemical risk for safety workersand their environment; thus, symptoms of exposure, preventionmeasures and protection tools are also described.     

Development and Evaluation of a Holistic and Mechanistic Modeling Framework for Chemical Emissions,Fate, Exposure,and Risk

Background: Large numbers of chemicals require evaluation to determine if their production and use pose potential risks to ecological and human health. For most chemicals, the inadequacy and uncertainty of chemical-specific data severely limit the application of exposure- and risk-based methods for screening-level assessments, priority setting, and effective management.Objective: We developed and evaluated a holistic, mechanistic modeling framework for ecological and human health assessments to support the safe and sustainable production, use, and disposal of organic chemicals.Methods: We consolidated various models for simulating the PROduction-To-EXposure (PROTEX) continuum with empirical data sets and models for predicting chemical property and use function information to enable high-throughput (HT) exposure and risk estimation. The new PROTEX-HT framework calculates exposure and risk by integrating mechanistic computational modules describing chemical behavior and fate in the socioeconomic system (i.e., life cycle emissions), natural and indoor environments, various ecological receptors, and humans. PROTEX-HT requires only molecular structure and chemical tonnage (i.e., annual production or consumption volume) as input information. We evaluated the PROTEX-HT framework using 95 organic chemicals commercialized in the United States and demonstrated its application in various exposure and risk assessment contexts.Results: Seventy-nine percent and 97% of the PROTEX-HT human exposure predictions were within one and two orders of magnitude, respectively, of independent human exposure estimates inferred from biomonitoring data. PROTEX-HT supported screening and ranking chemicals based on various exposure and risk metrics, setting chemical-specific maximum allowable tonnage based on user-defined toxicological thresholds, and identifying the most relevant emission sources, environmental media, and exposure routes of concern in the PROTEX continuum. The case study shows that high chemical tonnage did not necessarily result in high exposure or health risks.Conclusion: Requiring only two chemical-specific pieces of information, PROTEX-HT enables efficient screening-level evaluations of existing and premanufacture chemicals in various exposure- and risk-based contexts. https://doi.org/10.1289/EHP9372     

Environmental exposure scenarios: development, challenges and possible solutions

Under the new REACH system, companies importing, producing and marketing chemical substances will be obliged to register the single substances and to carry out a safety assessment for all identified uses during the life cycle of the substance. This duty will apply to about 10,000 existing substances in the EU market exceeding an annual production or import volume of 10 t per company. If the substance is already known to be dangerous or turns out to be dangerous(1) during the hazard assessment, the registrant is obliged to carry out an exposure assessment and a risk characterisation for all identified uses. The goal of the safety assessment is to define the conditions of use that allow for adequate control of risk with regard to health and safety at the work place, consumer safety and protection of the environment. Once the registrant has established and documented these conditions in the Chemicals Safety Report (CSR), that information is to be communicated down the supply chain by means of the Extended Safety Data Sheet (eSDS). The ultimate aim of the new legislation is to establish duties and mechanisms that systematically prevent or limit exposure to dangerous industrial chemicals. The current paper explains this concept with regard to environmental exposure and highlights the challenges and possible solutions.     

Industry's perception and use of occupational exposure limits

Market research was carried out to determine industry's perception of occupational exposure limits (OELs) and the extent to which they influence the selection of measures to control exposure. Telephone interviews were carried out with 1000 randomly selected users of chemicals, 400 from establishments with some use of chemicals and 600 from establishments with chemicals in daily use. 150 interviews were also carried out of Trade Union Health and Safety Representatives. The interviews covered basic information on chemicals used, sources of information, risk reduction measures used and understanding of COSHH and OELs.Most respondents came from firms with 10 employees or less (75%, all user group; 57%, heavy user group), closely reflecting the profile of British industry. In contrast, most (77%) Trade Union Health and Safety Representatives came from firms with at least 100 employees. Respondents in the all user group were drawn from across the whole range of industrial activity, whereas the heavy users were concentrated in manufacturing.The results showed that in making decisions on what control measures to use most users rely heavily on information from suppliers and personal experience and rather less on information from sources such as Trade Associations and HSE. Most respondents reported that steps were taken to protect employees. The use of personal protective equipment featured highly, followed by process controls. Little consideration was given to the possibility of substitution. Awareness of COSHH was limited with 65% of the all user group and 53% of the heavy user group being unaware of any legal requirements for establishments which manufacture or work with chemicals. Awareness of OELs was similarly limited with 19% of the all user group and 32% of the heavy user group having any real understanding. The results from Trade Union representatives showed that overall they are somewhat better informed than chemical users in the small firms surveyed.     

Risk of breast cancer among enlisted Army women occupationally exposed to volatile organic compounds

BACKGROUND: The military presents a unique opportunity to study the incidence of disease in a population with complete knowledge of person-time and occupation. Women in the Army are employed more frequently in non-traditional, industrial jobs such as auto mechanic and motor transport operators than in the general US population, increasing the probability of exposure to industrial chemicals. A cohort to investigate the risk of breast cancer among active duty Army women occupationally exposed to volatile organic chemicals (VOCs) was constructed. METHODS: Age-adjusted incidence rates for breast cancer were calculated for more than 270,000 enlisted women who served between 1980-1996. Twenty-one VOCs, described in previously published literature as having a potential risk of breast cancer, were identified in an Army industrial hygiene survey database. Job title histories were linked to workplace chemical evaluations conducted by Army industrial hygienists, which included a subjective exposure potential rating (high, medium, low, and none) for each VOC. Poisson regression analysis was used to evaluate the association between the exposure rating by job title and breast cancer. RESULTS: The incidence of breast cancer in the cohort was significantly elevated in women younger than 35 years of age, especially among black women, when compared to the age-specific rates in the general population. Women who worked in occupations with a moderate to high exposure potential to at least one VOC had a 48% increased risk (P < 0.05) of breast cancer while on active duty between 1980-1996 when compared to those women with low to no exposure potential. CONCLUSIONS: This study provides preliminary evidence that exposure to one or more of the study VOCs is associated with an increased risk of breast cancer. Further substance-specific, quantitative analyses are warranted.     

The Italian surveillance system for occupational cancers: characteristics, initial results, and future prospects

BACKGROUND: Occupational cancer monitoring is important for cancer prevention and public health protection. A surveillance system for identifying occupational cancer risks and cancer cases in Italy that are likely to be of occupational origin using information available in the Italian Social Security archives was created and assessed. Persons employed in the private sector, the employing company, its industrial sector, and years of employment are available in these archives. METHODS: A method to find known occupational hazards was first tested using a case-control approach. Cases were from six Italian cancer registries (CRs) and controls were sampled from source populations and as "exposure" the economic sector of the employing company was used. The potential of using hospital discharge records as case sources was subsequently assessed: these cover larger populations and are available more quickly than CR case series. RESULTS: In the CR-based study many known occupational cancer risks related to specific industrial sectors were identified. By using cases from hospital discharge records many industries at risk were identified, as well as cases of recent diagnosis likely to be of occupational origin. However, for some industrial sectors (e.g., the chemical industry) the approach was unable to detect any excess risk. Furthermore, information on employees in important areas like agriculture, self-employment, and the public sector is not available in the Social Security archives. CONCLUSIONS: This approach appears to be a promising low-cost method for occupational cancer surveillance, at least for some industries, and can be easily implemented in other countries.     

An overview of the use of quantitative structure-activity relationships for ranking and prioritizing large chemical inventories for environmental risk assessments

Ecological risk assessments for chemical stressors are used to establish linkages between likely exposure concentrations and adverse effects to ecological receptors. At times, it is useful to conduct screening risk assessments to assist in prioritizing or ranking chemicals on the basis of potential hazard and exposure assessment parameters. Ranking of large chemical inventories can provide evidence for focusing research and/or cleanup efforts on specific chemicals of concern. Because of financial and time constraints, data gaps exist, and the risk assessor is left with decisions on which models to use to estimate the parameter of concern. In this review, several methods are presented for using quantitative structure-activity relationships (QSARs) in conducting hazard screening or screening-level risk assessments. The ranking methods described include those related to current regulatory issues associated with chemical inventories from Canada, Europe, and the United States and an example of a screening-level risk assessment conducted on chemicals associated with a watershed in the midwest region of the United States.     

Assessment of exposure to cobalt and its compounds in Italian industrial settings

Background:Adverse health effects of occupational exposure to cobalt and its compounds are well-documented.Objectives:The aim of the study is to evaluate exposures to cobalt in Italian industrial settings.Methods:Data on cobalt and its compounds were collected from an occupational exposure registry. Statistical analysis was carried out for some exposure-related variables (i.e., cobalt compound, activity sector, occupational group, firm size). The number of workers potentially exposed was estimated for selected industrial sectors.Results:Overall 1,701 measurements were analyzed in the period 1996-2016. The geometric mean of cobalt airborne concentration was 0.33 µg/m³. Most exposures occurred in the manufacture of fabricated metal products (50%) and among metal finishing-, plating- and coating-machine operators (42%). A total of 30,401 workers potentially exposed to cobalt was estimated, over 72% were male.Conclusions:Identifying professional groups at high-risk of exposure can help to control the most dangerous situations for workers’ health. Surveillance systems based on occupational exposure registries contribute to support systematic improvement of working conditions.Key words: Carcinogenic risk, exposure assessment, prevention database, occupational health, surveillance systems     

Health hazards in the microelectronics industry

The microelectronics industry is explored as a source of occupational health hazards resulting from the extensive use of toxic chemicals in the production of semiconductor chips and the assembly of electronic components. Information is provided on the range of chemicals used in the industry and their particular health implications. Case materials are drawn from Massachusetts' "Route 128" region and California's "Silicon Valley." Problems with worker exposure in the plants are compared with the risks experienced by residents of local neighborhoods from the leakage of industrial chemicals from underground storage tanks into the local groundwater used for drinking water. The recent development of the industry, its highly innovative character, the absence of unions and organizations for worker protection, and the persistence of a public perception that the industry is relatively safe and clean, are all identified as determinants of the extent of health hazards posed by chemical exposure. The paper concludes with recommendations for further studies, worker organization, and increased attention to the reduction of the volume and toxicity of chemicals in industrial production.     

A proposed approach for setting occupational exposure limits for sensory irritants based on chemosensory models

OBJECTIVES: Setting occupational exposure limits (OELs) for odorous or irritating chemicals is a global occupational health challenge. However, often there is inadequate knowledge about the toxicology of these chemicals to set an OEL and their irritation potencies are usually not recognized until they are manufactured or used in large quantities. METHODS: In this paper, the importance of accounting for risk perception and communication; conditioned responses; and interindividual variability in tolerance, detection and susceptibility with respect to setting an OEL are discussed in relation to three chemosensory models. These parameters and models were then used to construct a flowchart-style methodology that can be used to set an OEL for a specific chemical. RESULTS: The OEL identified for a chemical odorant or irritant will depend on the type of chemosensory effect that the chemical is likely to exhibit. For example, experience has shown that chemicals with a low odor threshold often require low OELs even though many are not toxic or do not cause irritation at those air concentrations. CONCLUSION: In order to establish the appropriate OEL, organizations need to agree upon the percentage of the workforce that they are attempting to protect and the types of toxicological end points that are sufficiently important to protect against (e.g. transient eye irritation, enzyme induction or other reversible effects). This is particularly true for sensory irritants. The method described in this paper could also be extended to setting limits for ambient air contaminants where risk perception plays a dominant role in whether the public views the exposure as being reasonable or safe.     

Mode of action and aquatic exposure thresholds of no concern

Threshold concepts of toxicological concern are based on the possibility of establishing an exposure threshold value for chemicals below which no significant risk is to be expected. The objective of the present study is to address environmental thresholds of no toxicological concern for freshwater systems (ETNCaq) for organic chemicals. We analyzed environmental toxicological databases (acute and chronic endpoints) and substance hazard assessments. Lowest numbers and 95th-percentile values were derived using data stratification based on mode of action (MOA; 1 = inert chemicals; 2 = less inert chemicals; 3 = reactive chemicals; 4 = specifically acting chemicals). The ETNCaq values were derived by multiplying the lowest 95th percentile values with appropriate application factors; ETNCaq,MOA1-3 is approximately 0.1 microg/L. A preliminary analysis with complete MOA stratification of the databases shows that in the case of MOA1 or MOA2, the ETNCaq value could be even higher than 0.1 microg/L. A significantly lower ETNCaq,MOA4 value was observed based on the long-term toxicity information in the European Centre for the Ecotoxicology and Toxicology of Chemicals database. Application of the ETNCaq value in a tiered risk-assessment scheme may help chemical producers to set data-generation priorities and to refine or reduce animal use. It also may help to inform downstream users concerning the relative risk associated with their specific uses and be of value in putting environmental monitoring data into a risk-assessment perspective.     

Environmental impact on vascular development predicted by high-throughput screening

Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease.Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling.Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles.Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here.Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.     

Federal government regulation of occupational skin exposure in the USA

There are at least 14 federal regulations and three agencies that are involved in the regulation of occupational skin exposures in the USA. The Environmental Protection Agency (EPA) requires the reporting of health effects information on chemicals, and such information is used to assess the risks of human and environmental exposure. The health effects information and any resulting risk assessments are generally available to the public. A fair amount of this information relates to skin irritation, sensitization, and dermal absorption. The EPA can require the submission of new data necessary for it to carry out its risk assessments, and has the authority to ban hazardous chemicals for certain uses. The Food and Drug Administration (FDA) regulates the correct labeling of cosmetics and requires safety and efficacy data on new products that are claimed to have preventive or health benefits. Commercial distribution of topical skin-care and protection products, therefore, can be potentially scrutinized by the FDA, which can control the use of hazardous chemicals in such products. The Occupational Safety and Health Administration (OSHA) has the most direct contact with workplaces through its field inspection compliance activity, which is directed at the reduction of workplace injuries and illnesses. Our analysis suggests that although considerable amounts of health effects information is generated and available, such information may not always be adequately conveyed to the end users of chemical products. In addition, the most effective and practical means of preventing exposure is often not apparent or generally known. Current regulations may have created a reliance on use of chemical protective equipment that may not always be the best approach to protecting workers. Lack of performance criteria that are measurable has hampered industry from objectively assessing skin exposures. This lack of performance criteria or guidance has also hindered the implementation of prevention strategies and a critical assessment of their effectiveness. Better guidance from regulatory agencies directed at performance-based control of occupational skin hazards is presently needed.     

Inhalation risk upon exposure to emission from industrial enterprises in the town of Magnitogorsk

Based on the risk assessment methodology, the authors gives information on Magnitogorsk priority industrial enterprises; the chemicals contained in their emission from halation risk, which are responsible for moderare and severe risks. Negative health effects due to chronic inhalation exposure and the poorest environmental areas under observation are identified. The directions of application of the findings are specified.     

Health risk assessment and the practice of industrial hygiene

It has been claimed that there may be as many as 2000 airborne chemicals to which persons could be exposed in the workplace and in the community. Of these, occupational exposure limits have been set for approximately 700 chemicals, and only about 30 chemicals have limits for the ambient air. It is likely that some type of health risk assessment methodology will be used to establish limits for the remainder. Although these methods have been used for over 10 yr to set environmental limits, each step of the process (hazard identification, dose-response assessment, exposure assessment, and risk characterization) contains a number of traps into which scientists and risk managers can fall. For example, regulatory approaches to the hazard identification step have allowed little discrimination between the various animal carcinogens, even though these chemicals can vary greatly in their potency and mechanisms of action. In general, epidemiology data have been given little weight compared to the results of rodent bioassays. The dose-response extrapolation process, as generally practiced, often does not present the range of equally plausible values. Procedures which acknowledge and quantitatively account for some or all of the different classes of chemical carcinogens have not been widely adopted. For example, physiologically based pharmacokinetic (PB-PK) and biologically based models need to become a part of future risk assessments. The exposure evaluation portion of risk assessments can now be significantly more valid because of better dispersion models, validated exposure parameters, and the use of computers to account for complex environmental factors. Using these procedures, industrial hygienists are now able to quantitatively estimate the risks caused not only by the inhalation of chemicals but also those caused by dermal contact and incidental ingestion. The appropriate use of risk assessment methods should allow scientists and risk managers to set scientifically valid environmental and occupational standards for air contaminants.     

Evaluation of Biomonitoring Data from the CDC National Exposure Report in a Risk Assessment Context: Perspectives across Chemicals

Background: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals [NER; Centers for Disease Control and Prevention (2012)] provide information on the presence and concentrations of > 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment–based values now allow interpretation of these biomonitoring data in a public health risk context.Objectives: We compared the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER.Methods: We identified available risk assessment–based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQs) or cancer risk estimates.Conclusions: Most analytes in the NER show HQ values of < 1; however, some (including acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides) approach or exceed HQ values of 1 or cancer risks of > 1 × 10^–4 at the geometric mean or 95th percentile, suggesting exposure levels may exceed published human health benchmarks. This analysis provides for the first time a means for examining population biomonitoring data for multiple environmental chemicals in the context of the risk assessments for those chemicals. The results of these comparisons can be used to focus more detailed chemical-specific examination of the data and inform priorities for chemical risk management and research.     

Scrutinizing ACGIH risk assessments: the trichloroethylene case

BACKGROUND: The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLVs) for occupational exposure to chemicals and physical agents have been very influential in the setting of occupational exposure limits in many countries. METHODS: Three ACGIH risk assessments of the chlorinated solvent trichloroethylene (TCE) [ACGIH (1989): 5th edition; ACGIH (1992): 5th edition. Revised Vol II; ACGIH (1996): Suppl. 6th edition] are compared to 26 other risk assessments made of the same chemical substance. The documents are compared in terms of their overall conclusions and the data selected for assessment. RESULTS: It is shown that these ACGIH risk assessment documents were based on incomplete and biased data sets. CONCLUSIONS: The data on which the ACGIH [ACGIH (1996): Suppl. 6th edition] base their TCE risk assessment do not adequately reflect the available scientific knowledge about TCE toxicity and carcinogenicity. This may have influenced their conclusion that TCE is not carcinogenic in either animals or humans which stand out compared to contemporary risk assessments.