Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds

Abstract

Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated biphenyls (PCBs), dibenzo‐ρ‐dioxins (PCDDs), and dibenzofurans (PCDFs), are industrial compounds or by‐products that have been widely identified as environmental contaminants. Hazard and risk assessment of complex HAH mixtures have utilized a toxic equivalency factor (TEF) approach, where the toxic equivalents (TEQs) of any mixture are equal to the sum of the concentration of individual (i) congeners times their potencies (TEFi) relative to 2,3,7,8‐tetrachlorodibenzo‐ρ‐dioxin (TCDD, TEF = 1.0). TEQ = Σ [PCDDi] · TEFi + Σ [PCDFi] · TEFi + Σ [PCBi] · TEFi The TEQ (or TCDD equivalents) can be readily calculated from analytical data and provides an estimate of the toxicity of any mixture containing HAHs. Several in vivo and in vitro studies with some PCDD/PCDF and PCB mixtures have demonstrated correlations between experimentally determined and calculated TEQs. However, results of several studies have also shown that for specific responses, the TEQ for some HAH mixtures are non‐additive. For example, PCB mixtures and individual PCB congeners such as 2,2′,4,4′,5,5′‐hexachlorobiphenyl inhibit toxic and biochemical responses induced by TCDD and related compounds. Another problem associated with hazard and risk assessment of background exposure to HAHs is the relative contribution of trace levels of HAHs (exodioxins) compared to relatively high exposure to naturally occurring aryl hydrocarbon receptor (AhR) agonists, which act through the same mechanistic pathway. Teratogenesis Carcinog. Mutagen. 17:285–304, 1997/98. © 1998 Wiley‐Liss, Inc.

Toxicity of Mixtures of Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls Determined by Dose-Response Curve Analysis

“…Consequently, two possible explanations may contribute to our understanding of the mechanisms responsible for this nonadditive interaction: a) TCDD and PHAH (such as PCB77 and PCB153) might bind to different receptors and act through a different mechanism of action, therefore, the combined effects showed significantly non-additive interaction; b) TCDD and related PHAH (such as TCDF, PCB126) probably bind to the same Ah-receptor but act at different sites and induce different conformations of the Ahreceptor complex which exhibit different activities as nuclear transcription factors. The interactions of both potent and weak Ah receptor agonists to give nonadditive interactions has previously been reported from multiple laboratories and summarised in a recent review (Safe 1998). The non-additive antagonistic interactions between various PHAH are also consistent with results obtained for other ligand-induced transcription factors such as the estrogen receptor (ER) where PHAH such as PCB153: exhibit tissue specific weak ER aginist/antagonist activities (Ashby et al 1997;Gaido et al 1997;Ramamoorthy et al 1997).…”

Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat.

“…In our experiment, the MNU-TCDD treatment involved the administration of 87.5 ng TCDD (or 2.5 µg/kg bw) at day 18, and this did not inhibit tumor development. Three times less TCDD-toxic equivalents [TEQ (90,91)] were administered to the MNU-1,000× group (31.44 ng TCDD-TEQ divided in five doses over the first 20 days of life) than with the MNU-TCDD treatment, yet the MNU-1,000× group showed delayed tumor development. [The TCDD-TEQ value for the mixture was calculated using the mean volume of the mixture administered to the rats, the content of our mixture in Ah-R agonists, and their toxic equivalency factors (TEF) (PCB #77, 0.0001; #126, 0.1; #169, 0.01; #118, 0.0001; #156, 0.0005; #170, 0.0001, #180, 0.00005 (92)].…”

Long-Term Toxic Impact of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on the Reproduction, Sexual Differentiation, and Development of Different Life Stages of Gobiocypris rarus and Daphnia magna

“…It has been reported that TCDD exposure results in antiestrogenic activity and a!ects hormonal systems, but does not bind to estrogen receptors (Safe, 1998). Observed e!ects include delayed testis descent, impaired spermatogenic function, decreased accessory sex gland weights, and feminization of male sexual behavior (EPA, 1997;Solla et al, 1998).…”

“…At present, because of the extreme toxicity and high cost of developing standards, most studies on TCDD toxicity have involved short-term or one-time exposure (Mehrle et al, 1988;Wisk and Cooper, 1990;Spitsbergen et al, 1991;Walker et al, 1994;Cantrell et al, 1996;Henry et al, 1997;Elonen et al, 1998;Hornung et al, 1999). Therefore information on the relationship between EROD activity and TCDD exposure in di!erent developmental stages during long-term exposure to low dosage TCDD is lacking.It has been reported that TCDD exposure results in antiestrogenic activity and a!ects hormonal systems, but does not bind to estrogen receptors (Safe, 1998). Observed e!ects include delayed testis descent, impaired spermatogenic function, decreased accessory sex gland weights, and feminization of male sexual behavior (EPA, 1997;Solla et al, 1998).…”