The consultation noted that PCDDs, PCDFs, and the dioxin-like PCBs (non-ortho and mono-ortho substituted PCBs) exert a number of biochemical and toxicological effects mediated through the Ah receptor. Ah receptor binding affinity and responses directly dependent on Ah receptor activation suggest that humans may be less susceptible to TCDD than "responsive" rodent strains, whereas other biochemical or cellular effects are suggestive of a comparable susceptibility. The broad range of Ah-receptor binding affinities seen in human placenta samples suggests considerable variability of this parameter may exist within the general population.
A number of biochemical effects (CYP1A1/2 induction, EGFR down regulation, etc.) have been observed in experimental animals at body burden comparable to those of the general human population. These effects may or may not have implications for the toxicity of TCDD.
In the course of evaluating the adverse effects of dioxins at low doses, the usefulness of toxicokinetic and dose-effects modelling to calculate a "benchmark" (ED01) for comparison in the assessment was explored. It was noted that the outcome of using such models would strongly depend on the assumptions used and there are still a number of uncertainties in the interpretation of the results. Therefore, more traditional approaches using simple body burden calculations and empirical observations (LOAELs and NOAELs) have been used in this evaluation.
As discussed earlier, a wide variety of effects has been observed in studies of TCDD, and to a more limited extent of other PCDDs, PCDFs and dioxin-like PCBs, in animals and also in studies of complex mixtures of these compounds in human populations. For the purposes of a risk assessment of human exposure to dioxin-like compounds the consultation focused on effects seen at low doses. Table 1, Animal End-points non-cancer effects, presents a range of reported animal LOAELs which are considered adverse and which occur at body burdens in the range of 10-73 ng/kg. This suite of effects represents critical studies for the assessment of low dose effects of PCDDs/PCDFs.
Among these are developmental and reproductive effects in rats and monkeys. Responses are presented along with information on the increment to background body burdens in the experimental animals. These body burdens can readily be transformed into estimated daily human intakes that on a chronic basis would be expected to lead to similar body burdens in humans. Under steady state conditions, it is possible to estimate intakes as:
Intake (ng/kg/day) = Body Burden (ng/kg)*(ln(2)/half-life)/f
where f is the fraction of dose absorbed and is assumed to be 50% for absorption from food for humans, and an estimated half-life for TCDD of 7.5 years assumed. The results of such calculations appear in Table 4. Considering the very large differences in the half lives of dioxin-like compounds in various species, it is best to compare across species using this measure. It should be noted that the estimated human daily intakes are related to the body burdens in animals where adverse effects have been reported.
The consultation also considered a study of enhanced viral sensitivity in mice following acute exposure to TCDD but did not consider it appropriate for inclusion in the range of LOAELs as the lack of a dose-response relationship implies that there may be an unknown mechanism of action. In addition, children from Seveso with chloracne, who had been exposed acutely to high doses of TCDD, exhibited only minor transient alterations in various non-specific immune system parameters (see later). Similar analyses of sensitive responses in chronic animal cancer studies allow estimation of human daily intake values of about 150 pg/kg/day for the LOAEL (10 ng/kg/day) of the Kociba rat study corresponding to a body burden of 294 ng TCDD/kg, respectively. In addition to the adverse effects reported, numerous biochemical changes have been noted in experimental animals at body burdens within the range of 3-10 ng/kg. Several of these are also shown in Table 1. While these effects are observed at the lowest body burdens, they are considered to be early markers of events induced by dioxin-like compounds in animals and in humans and may or may not result in adverse effects.
In humans, maternal ingestion of high levels of a complex mixture of congeners from heat degraded PCBs (PCBs, PCDFs, PCQs) resulted in a variety of persistent severe adverse developmental and neurological effects in the infants. Maternal body burdens at the time of exposure were estimated to be 2-3 µg TCDD TEQs/kg. Non-cancer effects observed in mainly adult male workers occupationally exposed to high levels of TCDD and, to a lesser extent, higher chlorinated PCDDs included changes in serum lipids, elevated serum GGT, increased incidence of cardiovascular disease and diabetes. These effects were associated with mean body burdens at the time of last exposure ranging from 28-400 ng/kg.
TABLE 4. ANIMAL BODY BURDENS TCDD AND RELATED HUMAN ESTIMATED DAILY INTAKES (EDI)
|STUDY ||RESPONSE (LOAELs) ||MATERNAL BODY BURDEN*(ng/kg bw) ||RELATED HUMAN EDI(pg/kg bw/day) |
|- Gehrs, B.C., Riddle, M.M., Williams, W.C. and Smialowicz, R.J. Alterations in the developing immune system of the F344 rat after perinatal dioxin. II. Effects on the pup and the adult. Toxicology 122:229-240, 1997b.|
|- Gehrs, B.C. and Smailowicz, R.J. Persistent suppression of delayed-type hypersensitivity (DTH) in rats perinatally TCDD. Toxicologist 42:1501, 1998.|
|- Gray, L.E., Ostby, J.S. and Kelce, W.R. A TCDD) in male Long Evans hooded rat offspring. Toxicol. Appl. Pharmacol. 146:11-20, 1997a.|
|- Gray, L.E., Wolf, C., Mann, P. and Ostby, J.S. In utero TCDD) alters reproductive development of female Long Evans hooded rat offspring. Toxicol. Appl. Pharmacol. 146:237-244, 1997b.|
|- Rier, S.E., Martin, D.C., Bowman, R.E., Dmowski, W.P. and Becker, J.L. dioxin. Fundam. Appl. Toxicol. 21:433-441, 1993.|
|- Schantz, S. and Bowman, R.E. Learning in monkeys TCDD). Neurotoxicol. Teratol. 11:13-19, 1989.|
|Grey et al., 1997a ||RATS: decreased sperm count in offspring ||28 ||14 |
|Gehrs et al., 1997a; Gehrs et Smailowicz 1998 ||Inmune suppression in offspring ||50 ||25 |
|Grey et al., 1997b ||Increased genital malformations in offspring ||73 ||37 |
|Schantz and Bowman, 1989 ||MONKEYS:Neurobehaviourial (object lerning)effects in offspring ||42 ||21 |
|Rier et al., 1993 ||Endometriosis ||42 ||21 |
In Seveso residents (children and adults) acutely exposed to high levels of TCDD alone resulting in median serum lipid TCDD concentrations of 450 ng/kg in individuals in the zone of highest exposure (zone A), a variety of transient effects were seen including chloracne, increases in a serum enzyme activity (GGT) and alterations in lymphocyte counts. Studies on children from zone A did not reveal effects on immune competence. Mortality studies have indicated an excess of deaths due to cardiovascular diseases in males from zone A while an alteration in the sex ratio (excess females) of infants born to parents who both resided in zone A has also been reported.
As noted previously, back calculated blood concentrations of 2,3,7,8-TCDD determined in occupational cohorts which provide limited evidence of a human cancer response associated with dioxin exposure overlap with the blood concentrations determined in rats of the highest dose group (100 ng/kg/day) of the Kociba study. These and other data suggest that humans might be as sensitive as other animals to the adverse effects of dioxin and related compounds although data to evaluate comparable endpoints are frequently lacking.
The consultation recognized that the epidemiological evidence for the most highly TCDD-exposed cohorts studied produces the strongest evidence of increased risks for all cancers combined, along with less strong evidence of increased risks for cancers of particular sites. The relative risk for all cancers combined in the most highly exposed and longer latency sub-cohorts was 1.4. While the relative risk is not likely to be explained by confounding, this possibility cannot be excluded.
In the industrial populations or the population of Seveso in which cancer statistics were examined, the exposure to TCDD was higher by 2-3 orders of magnitude (to PCDD/DFs by 1-2 orders of magnitude) than that in the general population. The median body burdens associated with these exposures were 20 - 100 ng/kg.
The interpretation of the results from cohort studies concerning the effects on birth weight, maternal and new-born circulating thyroid hormones, and on the infant's developing nervous system is complicated by the simultaneous exposure to non-dioxin like PCBs (and maybe other compounds) that also might have played a significant role in eliciting these effects. These effects were observed at TEQ body burdens only slightly higher than that of the average general population, and thus point to the need for continuing efforts to reduce human exposure to these compounds, by controlling their input to the environment.