Ulf G. Ahlborg

Toxic equivalency factors for dioxin-like PCBs: Report on WHO-ECEH and IPCS consultation, December 1993

Abstract The WHO-European Centre for Environment and Health (WHO-ECEH) and the International Programme on Chemical Safety (IPCS), have initiated a project to create a data base containing information relevant to the setting of Toxic Equivalency Factors (TEFs), and, based on the available information, to assess the relative potencies and to derive consensus TEFs for PCDDs, PCDFs and dioxin-like PCBs. Available data on the relative toxicities of dioxin-like PCBs with respect to a number of endpoints were collected and analyzed. A consultation was held at the WHO-European Centre for Environment and Health in Bilthoven, the Netherlands, at which the available data were discussed to derive TEFs for dioxin-like PCBs. TEFs were recommended for 3 non- ortho -, 8 mono- ortho - and 2 di- ortho -substituted PCBs. The consultation recommended that the project should be extended to include PCDDs and PCDFs and other dioxin-like halogenated environmental pollutants. It was also recommended that the possibilities of separate TEFs for body burdens and ecotoxicology should be explored.

Organochlorine compounds in relation to breast cancer, endometrial cancer, and endometriosis : an assessment of the biological and epidemiological evidence

There is an increasing public and scientific concern that certain chlorinated compounds, recognized as environmental pollutants, may cause estrogen-related neoplastic disease in humans. The main hypothesis has been that certain organochlorines, through their estrogenic actions, might cause breast cancer. From experimental studies, both in vitro and in vivo, there is evidence that certain organochlorine compounds may cause estrogenic effects, whereas others may cause antiestrogenic effects. In limited studies, some of these compounds in high doses have also been shown to increase and reduce the frequency of estrogen-related tumors in animals. The epidemiological findings regarding the association between organochlorines and breast cancer are inconclusive. However, the largest and best designed study has been interpreted as negative with respect to DDT and polychlorinated biphenyls (PCB) in relation to breast cancer. Associations between organochlorine exposure and endometrial cancer or endometriosis have even more limited empirical basis. The hypothesis that human exposure to environmental levels or organochlorines would favor an estrogenic overactivity leading to an increase in estrogen-dependent formation of mammary or endometrial tumors is not supported by the existing in vitro, animal and epidemiological evidence. It can, however, not be conclusively rejected on the basis of available data.

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Impact of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls on human and environmental health, with special emphasis on application of the toxic equivalency factor concept

A scientific evaluation was made of the mechanisms of action of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls. Distinction is made between the aryl-hydrocarbon (Ah) receptor-mediated and non-Ah receptor-mediated toxic responses. Special attention is paid to the applicability of the toxic equivalency factor (TEF) concept.

Report of the WHO working group on the assessment of health risks for human infants from exposure to PCDDs, PCDFs and PCBs.

On Nov. 20-22, 1995, a World Health Organization working group consisting of 12 scientific representatives from 6 different countries met to reassess the health risks to infants associated with perinatal exposure to polyhalogenated aromatic hydrocarbons (PHAHs). Following a review of previous WHO/EURO consultations, as part of their comprehensive programme on PCDDs, PCDFs and PCBs, current exposure information and recent experimental and epidemiologic data were discussed. Exposure assessments within the past decade have revealed that in the case of breast milk samples concentrations of PCDDs/DFs and PCBs have shown a continual decline, in certain countries by up to 50%. New experimental data has revealed that a variety of structural, functional and behaviourial alterations can be induced in rodent species following exposure to PHAHs while a Dutch collaborative PCB/dioxin study has illustrated subtle clinical, endocrine and mental/psychomotor development effects can occur in breast fed infants. The provisional conclusions of the working group were: 1) current evidence does not warrant altering the previous WHO recommendation for promotion/support of breast feeding and 2) based on new clinical data which supports the biological plausibility of certain observed experimental observations, continued and enhanced effort should be directed towards identifying and controlling sources of environmental input for these contaminants.

TOXIC EQUIVALENCY FACTORS FOR DIOXIN-LIKE PCBs

Several PCDDs and PCDFs, as well as a few (dioxin-like) PCBs have been shown to exert a number of common toxic responses similar to those observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These include dermal toxicity, immunotoxicity, reproductive deficits, teratogenicity, endocrine toxicity, and carcinogenicity/tumour promotion. There is strong evidence suggesting a common mechanism of action of 2,3,7,8-TCDD and related compounds, based on a binding of these compounds to a specific receptor (the Ahreceptor). Due to the fact that dioxin-like compounds normally exist in environmental and biological samples as complex mixtures of congeners, the concept of toxic equivalents (TE Qs) has been introduced to simplify risk assessment and regulatory control. In applying this concept, relative toxicities of dioxin-like compounds in relation to 2,3,7,8-TCDD (i.e. toxic equivalency factors, TEFs) are determined based on in vitro and in vivo studies. This approach is based on the evidence that there is a common, receptor-mediated mechanism of action for these compounds.

Inhibition of metabolic cooperation in vitro and enhancement of enzyme altered foci incidence in rat liver by the pyrethroid insecticide fenvalerate

The synthetic pyrethroids cypermethrin, deltamethrin, fenvalerate, permethrin, and the fenvalerate metabolite p-chlorophenylisovaleric acid were investigated for inhibition of gap-junctional intercellular communication in vitro in the Chinese hamster lung fibroblast (V79) metabolic cooperation assay. Fenvalerate was furthermore studied for enhancement of gamma-glutamyl transpeptidase-positive enzyme altered foci incidence in partially hepatectomized, nitrosodiethylamine-initiated male Sprague Dawley rats. The in vitro studies showed that fenvalerate and p-chlorophenylisovaleric acid were inhibitors of intercellular communication at non-cytotoxic concentrations while cypermethrin, deltamethrin, and permethrin were inactive. In the in vivo study in rat liver, fenvalerate administered p.o. (75 mg/kg/day) 5 days a week for 10 weeks induced significantly more foci per cm3 and a larger percentage of liver tissue occupied by foci tissue compared to a vehicle control group. Analysis of size distributions of foci in fenvalerate- and vehicle-treated rats showed elevated foci incidences in fenvalerate-treated rats at all foci sizes. Fenvalerate induced no hepatotoxic effects as judged by plasma transaminase activities and histopathology. The results of this study suggest fenvalerate to be a potential tumour promoter.

Nordic risk assessment of PCDDs and PCDFs

Abstract The Nordic countries have performed a joint risk assessment of PCDDs and PCDFs. A tolerable weekly intake of 35 pg/kg body weight was considered appropriate and a new model for TCDD-equivalents was proposed. The consequences of the presented risk assessment is discussed.

Marked alterations in retinoid homeostasis of Sprague—Dawley rats induced by a single i.p. dose of 10 μg/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Interference of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in retinoid homeostasis was investigated in Sprague-Dawley rats with a low (dietary induced) retinoid status, that were fed a [3H]retinol-containing diet (37 MBq, 10,000 IU/kg diet) for 21 days to facilitate determination of retinoid concentrations in various tissues. The rats were exposed to a single i.p. dose of 10 micrograms TCDD/kg body weight in corn oil, or to corn oil at day 7 of [3H]retinol supplementation. TCDD induced significant reductions in retinol and retinyl ester concentrations and [3H] retinol-derived radioactivity in the liver, the lung, the intestine and the adrenals to 3-5%, 40-45%, 37%, and 56% of control values, respectively, at 14 days after exposure. In contrast, the retinoid concentrations and the amount of [3H]retinol-derived radioactivity in the kidney and serum of TCDD-treated rats was increased to 440% and 140% of corn oil-treated controls, respectively, at the termination time of the experiment. Analysis of the amount of serum retinol binding protein (RBP) by gel-permeation chromatography revealed an 150% increase in the free fraction of retinol-RBP, i.e., uncoupled to transthyretin (TTR), in serum of TCDD-treated rats. In addition, urinary excretion of [3H]retinol-derived radioactivity was significantly enhanced (to 140% of controls) by TCDD. These data indicate that TCDD induces an increased mobilization of retinoids from hepatic and extrahepatic storage sites into serum accompanied by an enhanced elimination via the kidney into the urine of rats.

Retinol (vitamin A) as an inhibitor of the mutagenicity of aflatoxin B1

Vitamin A (retinol) was shown to inhibit the mutagenic activity of aflatoxin B1 (AFB1), when added to the Ames Salmonella/mammalian microsome assay. The inhibition was dose-dependent and not caused by a direct toxic effect on the test bacteria. On the other hand the mutagenicity of diepoxybutane, a mutagen not requiring metabolic activation, was not affected by retinol, indicating that the vitamin does not act as a general scavenger of reactive compounds. The mutagenicity of AFB1 depends on the balance between formation and breakdown of aflatoxin 2,3-epoxide, the presumed ultimate mutagenic/carcinogenic metabolite. Inhibition of AFB1 mutagenicity could thus result from decreased formation or increased breakdown of the 2,3-epoxide.