title: 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.
authors.affiliation: Imperial College London, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Boobis
authors.forename: Robert
authors.initials: R
authors.lastname: Budinsky
authors.forename: Shanna
authors.initials: S
authors.lastname: Collie
authors.forename: Kevin
authors.initials: K
authors.lastname: Crofton
authors.forename: Michelle
authors.initials: M
authors.lastname: Embry
authors.forename: Susan
authors.initials: S
authors.lastname: Felter
authors.forename: Richard
authors.initials: R
authors.lastname: Hertzberg
authors.forename: David
authors.initials: D
authors.lastname: Kopp
authors.forename: Gary
authors.initials: G
authors.lastname: Mihlan
authors.forename: Moiz
authors.initials: M
authors.lastname: Mumtaz
authors.forename: Paul
authors.initials: P
authors.lastname: Price
authors.forename: Keith
authors.initials: K
authors.lastname: Solomon
authors.forename: Linda
authors.initials: L
authors.lastname: Teuschler
authors.forename: Raymond
authors.initials: R
authors.lastname: Yang
authors.forename: Rosemary
authors.initials: R
authors.lastname: Zaleski
mesh_terms: D019985:Benchmarking; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004784:Environmental Monitoring / Q000379:methods*; D004785:Environmental Pollutants / Q000737:chemistry / Q000592:standards / Q000633:toxicity*; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests / Q000379:methods / Q000592:standards
chemical_list: D004785:Environmental Pollutants