Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD)

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Abstract

We performed an analysis of All cancer and Lung cancer mortality in relation to estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) in the cohort of chemical workers at 12 US plants assembled by the US National Institute for Occupational Safety and Health (NIOSH) (n=5172). Estimates of cumulative exposure to TCDD were based on a minimal physiologic toxicokinetic model (MPTK) that accounts for inter- and intra-individual variations in body mass index (BMI) over time. Population-level parameters related to liver elimination and background (input or concentration) of TCDD were estimated from separate data with repeated measures of serum TCDD (US Air Force Health Study). An occupational TCDD input parameter was estimated based on one-point-in-time TCDD data available for a subset (n=253) of the NIOSH cohort. Model-based time-dependent cumulative dose estimates (area under the curve (AUC) of the lipid-adjusted serum TCDD concentration over time) were obtained for members of the full cohort with recorded body height and weight (n=4049), as this information is required by the MPTK model to compute dose. Missing-value problems arose in the estimation of the occupational input parameter (n=42) and in TCDD-dose calculation in the full cohort (n=886) and they were handled with multiple imputation methods. Risk-regression analyses were based on Cox log-linear models including age at entry, year of entry and duration of employment as categorical covariates in addition to the logarithm of cumulative TCDD dose in ppt-years. Risk sets were stratified on birth cohort. Estimates of the unlagged exposure coefficient in these models were 0.1249 [95% confidence interval (CI) 0.0144, 0.2354] for All cancer and 0.2158 (95% CI 0.02376, 0.4078) for lung cancer. A 10-year lag produced an increase in the estimate for all cancer (0.1539, 95% CI 0.0387, 0.2691), whereas, the estimate for lung cancer was not affected much (0.2125, 95% CI 0.0138, 0.4112). At a dose level of 100 times the background the estimates obtained with a 10-year lag translate into a relative risk of 2.03 (95% CI 1.19–3.45) for all cancer and of 2.66 (95% CI 1.07–6.64) for lung cancer. Higher estimates of the exposure coefficients were obtained after imputation of missing values. This increase in risk seemed due to the inclusion of short-term workers, who may exhibit a higher mortality for reasons other than dioxin exposure.

Introduction

Dioxins are chlorinated aromatic hydrocarbons of which the 2,3,7,8-isomer (tetrachlorodibenzo-p-dioxin or TCDD) is known for its multisite animal carcinogenicity. The International Agency for Research on Cancer (IARC) reviewed the available evidence for carcinogenicity and assigned TCDD to group one (human carcinogen) (IARC, 1997). In its review, IARC considered the evidence from human epidemiological data to be limited. However, the multisite cancer excess observed in occupationally exposed populations was found to be consistent with the animal evidence, based on likely similarities of the underlying biological mechanism (interaction with the aryl hydrocarbon (Ah) receptor, which is present in both animals and humans) (IARC, 1997). Exposed workers in the chemical industry provide exposure levels comparable to those observed in animal experiments. It is, therefore, of interest to estimate cancer risk as a function of TCDD dose in these occupational cohorts. The largest of these cohorts was assembled by the US National Institute for Occupational Safety and Health (NIOSH) and consisted of 5172 workers from 12 chemical plants in the United States. Cancer mortality in this cohort was first analyzed by Fingerhut et al. (1991), the observed cancer mortality excess for all cancer and lung cancer was found to be related to duration of exposure (time spent in TCDD-exposed jobs). All cancer mortality in this cohort was later analyzed by quantitative exposure scores and the excess for all cancer appeared to be restricted to workers with the highest exposures, at levels 100–1000 times those observed in the general population (Steenland et al., 1999).

In this paper we describe an analysis of all cancer and lung cancer mortality in the NIOSH cohort in relation to the estimated absorbed dose of TCDD.

Analyses based on estimated serum levels have been conducted on other cohorts with occupational exposure to TCDD (Ott and Zober, 1996, Becher et al., 1998, Hooiveld et al., 1998). In these analyses, past TCDD exposure levels were estimated based on statistical models of TCDD kinetics. These models rely on statistical adjustments via covariate control to account for deviation of TCDD kinetics from a fixed half-life (first-order) time behavior. In the analysis presented in this paper, we adopted a minimal physiological toxicokinetic model (MPTK) to estimate TCDD dose for individual members of the cohort. The model addresses long-term behavior of TCDD in humans and it was first proposed by Dankovic et al. (1995) and further analyzed by Thomaseth and Salvan, 1998, Salvan et al., 1999 and Bortot et al., 1999, Bortot et al., 2000. The model accounts for variations in lipid volume over time and how they affect the predicted lipid-adjusted serum concentration of TCDD. No covariate control is necessary to account for body mass and its changes or age. Unlike statistical models of TCDD kinetics (e.g. Flesch-Janys et al., 1996, Michalek et al., 1996), its parameters have a direct physiological meaning, however, without the complexity of mechanistic models for TCDD (e.g. Kohn et al., 1993), which typically require animal data as a source of parameter values.

In the following sections, we summarize our work on the MPTK model for TCDD and describe a mortality analysis for all cancer and lung cancer in the NIOSH cohort based on TCDD dose estimates obtained from the kinetic model.

Section snippets

The TCDD model

A detailed account and analysis of the MPTK model for TCDD first proposed by Dankovic et al. (1995) is reported elsewhere (Thomaseth and Salvan, 1998, Salvan et al., 1999, Bortot et al., 1999, Bortot et al., 2000). In the model, TCDD concentration is assumed to be in a dynamic equilibrium between three compartments of body lipids: blood; liver; and adipose tissue. Basic model assumptions are: (1) all TCDD elimination occurs in the liver with a fractional clearance rate which is proportional to

TCDD kinetic model

Parameter estimates for the TCDD kinetic model obtained under different methods are reported in Table 1. All estimation methods produced similar point and interval estimates of the liver-elimination parameter. A higher uncertainty seemed to be associated with the estimation of background input, probably because of the low amount of information on background levels contained in the Ranch Hand data. This difficulty was overcome in the Bayesian analysis (Bortot et al., 2000) which used an

Discussion

This mortality analysis of occupational cancer in relation to estimated absorbed dose of TCDD was based on dose estimates obtained from a minimal physiologic toxicokinetic model for TCDD. A special feature of the MPTK model is its ability to account for intra- and inter-individual variations of BMI over time and how they affect TCDD kinetics. This approach is a departure from that followed by others (e.g. Michalek et al., 1996, Flesch-Janys et al., 1996). The model is, however, built upon a

Conclusions

We presented a cancer mortality analysis in relation to estimated absorbed dose of TCDD. This study provided an example of interfacing an exposure model with a risk estimation model. Several limitations may have affected our analysis at different stages, as discussed above. However, our results appear to be generally consistent with those of other analyses of the same and of similar cohorts. Specifically, a sizable elevation (doubling) in risk for all cancer is obtained at TCDD doses that are

Acknowledgements

This work was partially supported by the National Institute for Occupational Safety and Health, Cincinnati, USA and by a grant from the Italian Ministero del Lavoro e della Previdenza Sociale. We thank J. Michalek for providing data from the Vietnam Veterans Health Study and K. Steenland, D. Dankovic and L. Stayner for comments and discussions at several stages of this project.

References (31)

  • D. Flesch-Janys et al.

    Elimination of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) in occupationally exposed persons

    J Toxicol Environ Health

    (1996)
  • M. Hooiveld et al.

    Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants

    Am J Epidemiol

    (1998)
  • IARC, International Agency for Research on Cancer. Working Group on the Evaluation of Carcinogenic Risks to Humans:...
  • International commission on radiation protection. The reference man

    (1975)
  • J.J. Knapik et al.

    Height, weight, percent body fat, and indices of adiposity in young men and women entering the US army

    Aviat Space Environ Med

    (1983)
  • Cited by (0)

    1

    Present address: Department of Statistics, University of Bologna, Via Belle Arti 41, Bologna 40126, Italy.

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