A very small proportion of all chemicals in commerce have occupational exposure limits (OELs) based on quantitative risk assessments which require estimates of exposure-response relationships (XRs). For only 18 of the 94 chemicals declared by NIOSH to be carcinogens were human XRs reported in or calculable from published reports. For the 18 carcinogens, 96 such XRs could be derived (corresponding to chemicals with multiple associated cancer end-points and/or multiple source studies). Twenty-four of 96 XR estimates came directly from reported statistical models (on continuous cumulative exposure), 45 were derived from summary study-population attributes, and 27 came from categorical analyses. Using the 96 XRs, OEL conferring one-per-thousand excess lifetime risk were calculated. OSHA's OEL, permissible exposure limits (PEL) were then compared to OEL derived from the 96 XRs. For 88 of the 96 calculated OELs (for which a corresponding PEL exists) all but 10 fell below the current PEL. Thirty-four OEL estimates were 10- to 100-fold below the PEL and 21 were greater than 100-fold below the PEL. This same pattern was observed using the different methods for deriving XRs. These findings can guide priorities in setting standards and the method is not limited to carcinogens.

BackgroundCancer and non-cancer associations have been observed with PFAS (perfluoroalkyl and polyfluoroalkyl) substances in the general population, in populations from locally contaminated environments and in exposed workers.MethodsA quantitative risk assessment on the PFAS substance perfluorooctanoic acid (PFOA) was conducted for six outcomes using two occupational mortality studies that reported sufficient data to estimate exposure-relationships in relation to serum PFOA levels. Excess lifetime mortality risks were calculated using a life table procedure that applies an exposure response to time-dependent PFOA serum levels for a surviving hypothetical population from ages 20 to 85. Both occupational and general population exposures were described as serum levels, and as air and drinking water concentrations.ResultsThe estimated occupational inhalation concentrations conferring the benchmark one-per-thousand lifetime risk were 0.21 µg/m3for chronic kidney disease, 1.0 µg/m3for kidney cancer and (from the two studies) 0.67 and 1.97 µg/m3for chronic liver disease. Specific excess lifetime risks estimated in the general population at current PFOA serum levels (~ 1 ng/mL) range 1.5–32 per 100 000 which corresponds to drinking water concentrations of less than 10 ppt.ConclusionOver eight outcome risk estimates, the serum PFOA concentrations conferring 1/1000 occupational lifetime risk ranged 44 to 416 ng/mL corresponding to air concentrations ranging 0.21 to 1.99 µg/m3. The analyses provide a preliminary PFOA quantitative risk assessment for liver and kidney disease mortality which, together with reported assessments for several other end-points, would inform policy on PFAS.

Diesel exhaust in the latter half of the 20th century has been found to be a lung carcinogen. Conventional diesel emissions continue in the transportation, mining, construction, and farming industries. From the Diesel Exhaust in Miners Study, a public-use dataset was used to calculate the excess lifetime risk of lung cancer associated with diesel exposure (1947-1997). Excess rates of lung cancer mortality associated with respirable elemental carbon (REC) and possible other mining exposures (e.g., oil mists, explosives emissions) were investigated using Poisson regression methods. Lung cancer mortality declined with increasing employment duration while increasing with cumulative REC and non-diesel exposures, suggesting a strong worker survivor effect. Attenuation of the REC effect was observed with increasing cumulative exposure. After adjustment for employment duration, the excess rate ratio for lung cancer mortality was 0.67 (95% CI = 0.35-0.99) for a 10-year lagged exposure to 200 μg/m3 REC, a typical below-ground exposure in the study mines. At exposures of 200, 10, and 1 μg/m3 REC, the estimated excess lifetime risks, respectively, were 119, 43, and 8.7 per thousand. Analysis of an inception cohort hired after dieselization commenced produced smaller and less certain estimates of lifetime risk. From exposures to conventional diesel engine exhaust common in occupational groups in the past, the excess lifetime risk of lung cancer was more than 5%. Ambient REC exposures in the general population were estimated to confer lifetime risks of 0.14 to 14 per thousand, depending on assumptions made.

An early epidemiologic study on groundwater contamination in the United States took place at an Environmental Protection Agency (EPA) Superfund site in Battle Creek Michigan. Volatile organic compounds (VOCs) consisting of chlorinated 2-carbon solvents were identified in private and municipal wells serving several communities. One major source of VOC was a solvent recovery operation near the municipal well field. The study modeled the VOC plume and investigated mortality and morbidity outcomes thought to be related to the VOC. Although quite statistically significant excess mortality and morbidity (hospital discharge and survey questionnaire) outcomes were observed, there were few associations with VOC water cumulative metrics. Another potentially dominant class of exposures could arise in VOC water contamination episodes from the diverse contents of spent solvents generated in multiple, local manufacturing activities. The findings at Battle Creek are re-interpreted in this light and the implications for Superfund-like investigation strategy and reporting are discussed.

The Continuous NHANES Survey provides detailed health and environmental chemical burden information on the U.S. population. As of 2012, there were data for 72,000 participants. Based on single biomarker determinations, cumulative burdens were estimated. Because age distributions would differ comparing ambient environmental and occupational exposures, a procedure to distinguish ambient from likely occupational exposures was applied. Associations are reported for osteoporosis and kidney disease-related outcomes with cadmium, lead, and other metals. Cumulative cadmium burden (from blood cadmium, ambient and occupational) was a strong predictor of bone fracture risk and ambient tungsten also had a positive association. Cumulative lead (ambient and occupational) had a negative ("protective") association with fractures as did mercury (occupational). Bone mineral density was statistically significant and similarly predicted by metal exposures. Kidney disease was significantly associated with cumulative lead burdens from both the estimated ambient and occupational sources and with ambient blood cadmium but was most strongly associated with cumulative occupational uranium burden. Systolic blood pressure statistically significantly increased with cumulative ambient and occupational lead (blood) burden and with ambient cadmium and cobalt. Diastolic blood pressure was significantly associated with several cadmium and cobalt metrics along with ambient and occupational cumulative burdens for lead. For environmental substances with burden half-lives measured in years, NHANES offers opportunities for hypothesis generation and confirmation.

Background: Toluene diisocyanate (TDI) is a highly reactive chemical that causes sensitization and has also been associated with increased lung cancer. A risk assessment was conducted based on occupational epidemiologic estimates for several health outcomes. Methods: Exposure and outcome details were extracted from published studies and a NIOSH Health Hazard Evaluation for new onset asthma, pulmonary function measurements, symptom prevalence, and mortality from lung cancer and respiratory disease. Summary exposure-response estimates were calculated taking into account relative precision and possible survivor selection effects. Attributable incidence of sensitization was estimated as were annual proportional losses of pulmonary function. Excess lifetime risks and benchmark doses were calculated. Results: Respiratory outcomes exhibited strong survivor bias. Asthma/sensitization exposure response decreased with increasing facility-average TDI air concentration as did TDI-associated pulmonary impairment. In a mortality cohort where mean employment duration was less than 1 year, survivor bias pre-empted estimation of lung cancer and respiratory disease exposure response. Conclusion: Controlling for survivor bias and assuming a linear dose-response with facility-average TDI concentrations, excess lifetime risks exceeding one per thousand occurred at about 2 ppt TDI for sensitization and respiratory impairment. Under alternate assumptions regarding stationary and cumulative effects, one per thousand excess risks were estimated at TDI concentrations of 10 - 30 ppt. The unexplained reported excess mortality from lung cancer and other lung diseases, if attributable to TDI or associated emissions, could represent a lifetime risk comparable to that of sensitization. (C) 2020 Occupational Safety and Health Research Institute, Published by Elsevier Korea LLC.

BACKGROUND Elevated bladder cancer incidence has been reported in a cohort of 1875 workers manufacturing chemicals used in the rubber industry and employed any time during 1946-2006. o-Toluidine (OT), an aromatic amine, was the prime suspect agent. Using the available environmental data and process characterization, previous investigators assigned ranks to volatile chemical air concentrations across time in departments and jobs, reflecting probabilities of exposure and use of personal protective equipment for airborne and dermal exposures. Aniline, another aromatic amine, was present at comparable concentrations and is known to be an animal carcinogen but produced lower levels in post-shift urine and of hemoglobin adducts than OT in a group of workers. METHODS A quantitative risk assessment was performed based on this same population. In this study, cumulative OT exposures were estimated (a) based on previously assigned ranks of exposure intensity and reported actual exposures in jobs with the highest assigned rank, and (b) directly from the historical environmental sampling for OT. Models of bladder cancer incidence were evaluated taking into account possible healthy worker survivor effects. RESULTS Under various assumptions regarding workforce turnover, the excess lifetime risk of bladder cancer from OT exposure at 1 ppb was estimated to be in the range 1-7 per thousand. CONCLUSIONS The current ACGIH TLV and OSHA standards for OT are 2 and 5 ppm, respectively, 1000-fold higher than the exposure estimated here for 1-7 per thousand excess lifetime risk.

Background Toluene diisocyanate (TDI) is a highly reactive chemical that causes sensitization and has also been associated with increased lung cancer. A risk assessment was conducted based on occupational epidemiologic estimates for several health outcomes. Methods Exposure and outcome details were extracted from published studies and a NIOSH Health Hazard Evaluation for new onset asthma, pulmonary function measurements, symptom prevalence, and mortality from lung cancer and respiratory disease. Summary exposure–response estimates were calculated taking into account relative precision and possible survivor selection effects. Attributable incidence of sensitization was estimated as were annual proportional losses of pulmonary function. Excess lifetime risks and benchmark doses were calculated. Results Respiratory outcomes exhibited strong survivor bias. Asthma/sensitization exposure response decreased with increasing facility-average TDI air concentration as did TDI-associated pulmonary impairment. In a mortality cohort where mean employment duration was less than 1 year, survivor bias pre-empted estimation of lung cancer and respiratory disease exposure response. Conclusion Controlling for survivor bias and assuming a linear dose–response with facility-average TDI concentrations, excess lifetime risks exceeding one per thousand occurred at about 2 ppt TDI for sensitization and respiratory impairment. Under alternate assumptions regarding stationary and cumulative effects, one per thousand excess risks were estimated at TDI concentrations of 10 – 30 ppt. The unexplained reported excess mortality from lung cancer and other lung diseases, if attributable to TDI or associated emissions, could represent a lifetime risk comparable to that of sensitization.

Acrylamide (ACM) is a high-volume industrial chemical with diverse uses in manufacturing, construction and laboratory research. ACM is a well-established neurotoxic agent causing peripheral neuropathy with impairment in the arms and legs of exposed workers, most thoroughly studied in Swedish tunnel workers exposed to ACM grouting. A quantitative risk assessment was performed to assess ACM risk to workers. Using data from a published paper investigating peripheral neuropathies in Chinese chemical workers, estimates of exposure response for vibration perception threshold and nerve conduction velocities were calculated, based on hemoglobin adducts and air concentrations as exposure metrics. The benchmark dose procedure was applied in order to calculate excess risks of impairment, defined as adverse performance exceeding the 95th percentile in unexposed populations, at various concentrations of airborne ACM exposure. Under the assumptions in this risk assessment, after three years of inhalation exposure at 0.3 mg/m3, the excess attributable impairment manifest in vibration perception and nerve conduction velocity is estimated to occur in 1-2% of workers. For 10 years at 0.3 mg/m3 ACM inhalation (equivalent to 3 years at 1.0 mg/m3) the excess prevalence of impairment would be 2-14% of workers, assuming the effect continues to accrue linearly in time. Using published data, the risks of impairment from peripheral neuropathy attributable to exclusively airborne ACM exposure can be predicted for exposure periods less than 10 years. The risks associated with dermal and airborne ACM exposures can be estimated by characterizing working process environments using ACM Hb-adduct levels and possibly monitored with urinary biomarkers.

BACKGROUNDPrevious analyses of mortality were conducted in a large cohort of ethylene oxide (EtO) exposed workers employed at 13 sterilization facilities throughout the U.S. and followed from the start of operation through 1998. Statistically significant elevated mortality was reported from hematopoietic cancer in men and breast cancer in women compared to the general population. Possible healthy worker survivor bias was not addressed.METHODSTo examine survivor bias in this cohort, employment termination was analyzed with statistical models stratified on sex and race that included age, employment duration, and cumulative EtO exposure. To reduce survivor bias employment duration was included in Poisson regression model specifications for estimating standardized mortality ratios for several cancer outcomes.RESULTSStrong statistically significant effects of unlagged cumulative EtO exposure were observed on rate of employment termination, indicating potential healthy worker survivor effect bias. Adjustment for employment duration in analyses of mortality resulted in statistically significant and stronger associations between cumulative EtO exposure and lung cancer, female breast cancer and hematopoietic cancer. There was a striking reduction in nonmalignant respiratory disease mortality risk with increasing employment duration with a further (nonsignificant) reduction with cumulative EtO, suggesting that EtO itself is driving termination of workers with respiratory morbidity even though the average EtO exposures in this population were generally far below odor and acute irritancy thresholds.CONCLUSIONSImportant survivor bias was present in this EtO cohort and may be present in many occupational settings involving irritant exposures.

Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose-dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low-dose exposure response in chronic exposure. A simple one-compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up- or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.

Background Metalworking fluids (MWF) are complex mixtures with dermal and inhalation exposure. Published reports reveal excess cancer risk. Methods Using published findings exposure response was derived for each attributable cancer site. Aggregate excess lifetime risk was estimated by applying a lifetable calculation. Results Cancer sites contributing the most attributable cases were larynx, esophagus, brain, female breast, and uterine cervix. With constant workplace MWF exposure of 0.1 mg/m 3 over a 45 years working life, the risk of attributable cancer was 3.7% or, excluding the less certain female cancers, 3.1%. Conclusion Substantial cancer risks occurred at 0.1 mg/m 3 MWF, one fourth of the current NIOSH recommended exposure limit for MWF total particulate. Because ingredients in current MWF remain from earlier formulations, it is likely that some MWF carcinogenicity persists today. Although important changes have occurred, newer agents are being continually introduced with little or no knowledge of chronic health risks.

Objectives:The butter flavoring additive, diacetyl (DA), can cause bronchiolitis obliterans (BO) by inhalation. A risk assessment was performed using data from a microwave popcorn manufacturing plant.Methods:Current employees' medical history and pulmonary function tests together with air sampling over a 2.7-year period were used to analyze forced expiratory volume in 1second (FEV1) and FEV1/forced vital capacity (FVC). The exposure responses for declining pulmonary function and for possible early onset of BO were estimated using multiple regression methods. Several exposure metrics were investigated; benchmark dose and excess lifetime risk of impairment were calculated.Results:Forty-six percent of the population had less than 6 months exposure to DA. Percent-of-predicted FEV1 declined with cumulative exposure (0.40 per ppm-yr, P<10(-7)) as did percent FEV1/FVC (0.13 per ppm-yr, P=0.0004). Lifetime respiratory impairment prevalence of one per thousand resulted from 0.005ppm DA and one per thousand lifetime incidence of impairment was predicted for 0.002ppm DA.Conclusion:DA exposures, often exceeding 1ppm in the past, place workers at high risk of pulmonary impairment.

Similar patterns of cognitive and motor deficits have been widely reported from manganese exposures in welding, metallurgical and chemical industry workers. A risk assessment was performed based on studies reported in the literature, extending some earlier work, and deriving new estimates of exposure response and excess risk. Many investigations of manganese neurological effects in humans have insufficient information to derive an exposure response; however, findings from a chemical manufacturer, two smelter and two welder populations permitted application of the benchmark dose procedure for continuous end-points. Small particles and aggregates of condensation fume (condensing vaporized metal, <0.1 μm in diameter) appear to have a higher potency per unit mass than larger particles from dusts (>1.0 μm). Consideration was given to long-term effects of continuous low exposures that instead of producing increasing toxicity attain a steady-state condition. Impairment was defined as excursions beyond the 5th percentile in a normal population and the concentrations of manganese predicted to result in 1% excess prevalence of impairment over different time periods were calculated. Over five years, exposures resulting in 1% excess prevalence of impairment (for purposes of discussion) were in the vicinity of 10 μg/m3 for manganese fume and 25 μg/m3 for larger particle dusts. These levels are below current recommendations for occupational limits on manganese exposure in the United States.

Quantitative risk assessment often begins with an estimate of the exposure or dose associated with a particular risk level from which exposure levels posing low risk to populations can be extrapolated. For continuous exposures, this value, the benchmark dose, is often defined by a specified increase (or decrease) from the median or mean response at no exposure. This method of calculating the benchmark dose does not take into account the response distribution and, consequently, cannot be interpreted based upon probability statements of the target population. We investigate quantile regression as an alternative to the use of the median or mean regression. By defining the dose-response quantile relationship and an impairment threshold, we specify a benchmark dose as the dose associated with a specified probability that the population will have a response equal to or more extreme than the specified impairment threshold. In addition, in an effort to minimize model uncertainty, we use Bayesian monotonic semiparametric regression to define the exposure-response quantile relationship, which gives the model flexibility to estimate the quantal dose-response function. We describe this methodology and apply it to both epidemiology and toxicology data.

Studies in railroad workers, truck drivers, and miners reveal diesel exhaust to be carcinogenic. Although technology has evolved, a large capacity in the U.S and globally still comprises traditional diesel engine design in transportation, mining, construction and farming. The Diesel Exhaust in Miners Study (DEMS) with an extensive exposure assessment investigated 200 lung cancer deaths in non-coal and non-metal miners. A DEMS dataset was used to calculate the excess lifetime risk for airborne concentrations of respirable elemental carbon (REC). A healthy worker survivor effect and possible confounding by non-diesel power generation and other mining exposures (e.g., explosives) were investigated along with dose-rate effects using Poisson regression methods with high-resolution classification. Lung cancer mortality declined with employment duration and more so when REC and non diesel exposure effects were also estimated, revealing a strong survivor bias. Attenuation of the REC effect was also observed with increasing (lagged) cumulative REC exposure. In underground miners, the excess relative rate of lung cancer mortality was 0.67 (p 3 REC, a typical underground exposure. At occupational REC exposures of 200, 10 and 1 µg/m 3 the excess lifetime risks, respectively, were 119, 43 and 8.7 per thousand. The estimated lifetime risk was greater than some previous estimates not accounting for heathy worker survival bias. This bias was addressed using employment duration and mine above/below ground status. A model-fitted function of cumulative exposure accommodated attenuation of exposure effect. The estimated excess lifetime risks of lung cancer at old diesel REC exposure levels common in occupational groups in the past exceed 5%.

MWF mixtures vary across manufacturing process, facilities, enterprises and over time. The routes of exposure are dermal in liquid phase, and inhalation as dusts, mists and vapours. The challenge is to generalise from specific worker populations observed over many decades and from animal studies limited to few priority components. Cancer risks have been observed in both hazard identification and exposure-response studies. Respiratory disorders and performance deficits are other health effects of MWFs appearing as increased morbidity and mortality or reduced pulmonary function, as well as immune-mediated disorders: adult-onset asthma and hypersensitivity pneumonitis (HP). Dermatitis has been a constant associate of MWFs for more than two centuries. The goal here was to explore the development of a generic summary of MWF effects to determine exposure levels conferring an acceptable low level of risk in most metalworking environments. Only total gravimetric measures of airborne dusts or mists were considered, usually with restriction to the respirable fraction. Aggregate cancer excess risk was estimated from the few studies with adequate retrospective exposure assessments and work history. Lifetime risk was calculated. Annual proportional loss of respiratory capacity was evaluated, using a benchmark dose procedure. Incidence of asthma and hypersensitivity pneumonitis (HP) was examined as were aggregate symptoms focusing largely on respiratory complaints. For MWF exposure to 0.1 mg/m 3 over 45 yr, the lifetime risk of attributable cancer was about 3.5% and attributable respiratory impairment would occur in 4.5% of workers. Lifetime risk of asthma or HP (under outbreak conditions) was 80% at 0.1 mg/m 3 . After 45 yr at 0.1 mg/m 3 MWF, excess prevalence of primarily respiratory symptoms would be 9 percent based on published studies, and 20 percent from NIOSH investigations.

publication, Evaluation of electronic cigarette liquids and aerosol for the presence of selected inhalation toxins . 1 recognizing the high rate of chronic obstructive pulmonary disease and of bronchiolitis, specifically, in smokers and for measur-ing the concentrations of diacetyl (DA) and acetyl propionyl (AP, also known as 2,3-pentanedione) in electronic cigarette (e-cigarette) liquids and aerosols. we

Virtually no occupational exposure standards specify the level of risk for the prescribed exposure, and most occupational exposure limits are not based on quantitative risk assessment (QRA) at all. Wider use of QRA could improve understanding of occupational risks while increasing focus on identifying exposure concentrations conferring acceptably low levels of risk to workers. Exposure-response modeling between a defined hazard and the biological response of interest is necessary to provide a quantitative foundation for risk-based occupational exposure limits; and there has been considerable work devoted to establishing reliable methods quantifying the exposure-response relationship including methods of extrapolation below the observed responses. We review several exposure-response modeling methods available for QRA, and demonstrate their utility with simulated data sets.