Kim H. Kreckmann

Cross-sectional Study of Lipids and Liver Enzymes Related to a Serum Biomarker of Exposure (ammonium perfluorooctanoate or Apfo) as Part of a General Health Survey in a Cohort of Occupationally Exposed Workers

Objective: To examine the relationship between serum perfluorooctanoate (PFOA), a biomarker of ammonium perfluorooctanoate (APFO) exposure, and lipids and liver enzymes in a cross-sectional study among workers with potential occupational exposure to APFO. Methods: We conducted a cross-sectional study of 1025 active workers with potential exposure to APFO using linear regression to examine the relationship between PFOA and selected outcomes from a standard metabolic health screening survey, emphasizing lipids and liver enzymes. Results: Most outcome parameters were within normal limits. After adjusting for potential confounders, we observed a modest but statistically significant, positive relationship between serum PFOA and total cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and gamma glutamyl aminotransferase (GGT). No associations were seen for high-density lipoprotein (HDL) or bilirubin; associations with AST (aspartate aminotransferase) and ALT (alanine transpeptidase) did not reach statistical significance. Conclusions: Our findings indicate a modest positive association of PFOA on some lipid parameters and a need for follow-up studies.

Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate.

Objective: To examine the relationship between serum perfluorooctanoate (PFOA), a biomarker of ammonium perfluorooctanoate exposure, and lipids and liver enzymes. Methods: We conducted a longitudinal study on 454 workers and used mixed models to examine the relationship between serum PFOA and lipids and liver enzymes. Results: One part per million (ppm) increase in serum PFOA was associated with a 1.06 mg/dL increase in total cholesterol, but was not associated with changes in triglycerides or other lipoproteins, after adjusting for potential confounders. Serum PFOA was also associated with total bilirubin (0.008 mg/dL decline/ppm) and serum aspartate aminotransferase (0.35 units increase/ppm) but not with the other liver enzymes. Conclusions: These medical surveillance data collected on workers for up to 25 years contributes useful information on the effects of ammonium perfluorooctanoate exposure on human liver and lipid chemistry.

Ischaemic heart disease mortality study among workers with occupational exposure to ammonium perfluorooctanoate

Objectives: Ammonium perfluorooctanoate (APFO) is a biopersistent surfactant used in the manufacture of several types of fluoropolymers. Based on previous findings of increased serum lipid levels associated with exposure to APFO, we evaluated ischaemic heart disease (IHD) mortality in a cohort of occupationally exposed workers. Methods: Relative risks (RR) were estimated from exposure–response analyses of cumulative exposure measures using proportional hazards regression models. Results: 239 IHD deaths have occurred in the cohort of 4747 workers with work histories from 1948 through 2002. RR estimates indicate no statistically significant increased mortality risk for IHD associated with estimated cumulative exposure. We observed a positive trend only at an exposure lag of 10 years. This finding was not reproduced in other 5-year exposure lags and was attenuated when different cutpoints for exposure categorisation were used. Conclusion: This exposure–response study shows no convincing evidence of increased IHD mortality risk for APFO-exposed workers at this plant. Further studies evaluating the incidence of IHD are being conducted.

Inhalation developmental toxicity and reproduction studies with cyclohexane

The reproductive and developmental toxicity of cyclohexane was assessed in a two-generation reproduction study with Crl:CD® BR rats and in developmental toxicity studies with Crl:CD®BR rats and Hra:(NZW)SPF rabbits. The animals were exposed whole-body to atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane. In the two-generation reproduction study, parental effects included statistically significantly lower mean body weight, overall mean body weight gain, and overall mean food efficiency for P1 and F1 females of the 7000 ppm level and statistically significantly lower mean body weight for F1 males of that level. Adult rats exposed to 2000 ppm cyclohexane and above exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Mean pup weight was statistically significantly lower than control from lactation day 7 throughout the remainder of the 25-day lactation period for both F1 and F2 7000 ppm litters. Changes observed at 500 ppm were either considered not to be compound related or not adverse. Therefore, the systemic-toxicity no-observed-effect level (NOEL) was 500 ppm and the reproductive NOEL was 2000 ppm. The reproductive NOEL was based solely on the decreased pup weights in both the F1 and F2 generations observed at 7000 ppm. In the developmental toxicity studies, only the rats showed evidence of maternal toxicity. For rats in the 7000 ppm group, statistically significant reductions were observed in overall maternal body weight gain and overall maternal food consumption for the treatment period. Rats exposed to 2000 ppm cyclohexane and above again exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Therefore, for rats, the maternal no-observed-effect level (NOEL) was 500 ppm. In the rabbit developmental toxicity study, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore, the maternal NOEL for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration in either species. Therefore, the developmental NOEL for both species was 7000 ppm, the highest concentration tested.

Mortality among workers exposed to acrylonitrile in fiber production: an update.

Objective: The investigation updates the mortality experience through 2002 for a cohort of workers exposed to acrylonitrile (AN). Methods: Standardized mortality ratios (SMR) were estimated based on two reference populations: the US population and a regional employee population. Exposure–response analyses were conducted using Cox regression models for cumulative and mean intensity exposure measures. Results: In the cohort of 2548 workers, 839 deaths have occurred with 91 deaths due to respiratory system cancer. Most standardized mortality ratio estimates are at or near no-effects levels. Hazard ratio (HR) estimates indicate no increased mortality risk for respiratory system cancer (adjusted HR = 0.96, 95% confidence interval: 0.74, 1.25). Conclusions: In summary, no mortality outcome of a priori interest, principally respiratory system cancer, is associated with increased AN exposure among fiber production workers over five decades of follow-up.

0112 Components of the Healthy Worker Effect with Quantification for Different Referent Comparisons

Objectives The healthy worker effect (HWE) is widely known to bias standardised risk estimates from occupational cohort studies. Multiple factors contribute to HWE bias that is commonly characterised as confounding due to the selection of individuals with “better health status” who are more likely to gain and retain employment relative to a general population including non-employed persons. Comparisons between standardised mortality ratios (SMRs) estimated from reference population rates with different characteristics allow for quantitative evaluation of different components of the HWE. Method Data from over five decades for a company-wide mortality registry comes from life insurance claims, and deaths are validated against the U. S. National Death Index. Average person-years at risk during five-year calendar periods for the occupational cohort population are estimated. The expected mortality counts are specific to age, sex, race, and calendar-time period strata. SMRs are calculated based on the mortality rates for the general U. S. population and the company-wide population. Results From 1956 through 2012, the annual US employee population has ranged from 29 000 to 108 000 workers. The mortality registry includes over 80 000 deaths validated through 2010, 25% due to malignant neoplasms and 37% due to cardiovascular diseases. Conclusions The HWE influences the interpretation of standardised estimates from occupational studies. Comparisons for different reference populations can evaluate differential HWE bias of associations between occupational exposure and mortality. Analyses based on company reference rates identify contributions from components of the HWE based on comparable demographic characteristics, a similar likelihood of obtaining and retaining employment, and an equivalent potential for ascertainment of mortality outcomes.