Derivation of internal dose-based thresholds of toxicological concern for occupational inhalation exposure to systemically acting organic chemicals

Abstract

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61 × 10⁻² and 9 × 10⁻⁴ mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55 × 10⁻¹ and 8.5 × 10⁻³ mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r² = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.

Keywords:

• Data-poor chemicals
• occupational health risk assessment
• PBPK modeling
• quantitative property-property relationship
• threshold of toxicological concern

Acknowledgments

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Dr. Kannan Krishnan’s research on quantitative structure-property relationships for developing PBPK models is supported by a Discovery grant from the Natural Sciences and Engineering Research Council of Canada.