Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment

Abstract

There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.

Keywords::

• Chemical mixtures
• low dose
• risk assessment
• synergy
• TTC

Acknowledgements

The authors would like to thank Drs. Roger Meyerhoff and Joel Bercu (Eli Lilly) for valuable review, input, and edits and Drs. Jason Lambert (US EPA) and Ed Carney (Dow Chemical) for their thoughtful reviews.

Declaration of interest

The employment affiliations of the authors are shown on the cover page. These individuals had the sole responsibility for the writing and content of the paper. The individual authors worked as professionals in preparing the article and not as agents of their employers. The literature review used as the basis of this article was performed by three of the authors (R.H., S.C., and D.K.) and funded by the HESI Mixtures Committee, which collects funding from member companies to support the project. Four of the authors (A.B., D.K., K.S., and R.Y.) are affiliated with universities, two authors (R.H. and S.C.) are independent consultants providing services to public and private organizations, three of the authors* are affiliated with government agencies, one author (M.E.) is affiliated with a nonprofit organization and six of the authors (R.B., S.F., G.M., P.P., and R.Z.) are employed by private corporations. Government and academic committee participants were reimbursed for travel expenses to attend committee meetings and did not receive any other compensation. (*The views expressed in this paper are those of the authors and do not necessarily reflect the opinions or policy of the US EPA or the Centers for Disease Control, ATSDR.)

Notes

¹It is noted that the PEL is equivalent to the TLV for ethylbenzene and xylenes (100 ppm for all values); it is 4-fold higher than the TLV for toluene (200 ppm vs. 50 ppm).