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Dioxins

6. Evaluation and conclusions

  • 6.1 Human exposure to Dioxins
  • 6.2 Observed health effects
  • 6.3 Tolerable Daily Intake set by WHO for dioxins
    • 6.3.1 How did WHO derive the intake limit?
    • 6.3.2 How must this limit be understood?
  • 6.4 Breastfeeding

6.1 Human exposure to Dioxins

    • 6.1.1 Exposure
    • 6.1.2 Toxicokinetics

6.1.1 Exposure

The source document for this Digest states:

Substantial information on the concentrations of PCDDs/PCDFs and limited information on dioxin-like PCBs in environmental samples, foods, human tissues, as well as breast milk are available for a number of mainly industrialized countries. The information indicates that the concentrations of these compounds have decreased during the last 10 years, mainly due to enforced regulations that have limited their dispersal to the environment and hence the food chains.

The available information derived from food surveys in numerous industrialized countries indicates a daily intake of PCDDs and PCDFs in the order of 50-200 pg I-TEQ/person/day, or 1-3 pg I-TEQ/kg bw/day for a 60 kg adult. This intake results in average human tissue levels in the range of 10-30 pg I-TEQ/g lipid, equivalent to a body burden of 2-6 ng I-TEQ/kg body weight. If the dioxin-like PCBs (non-ortho and mono-ortho PCBs) are also considered, the daily TEQ intake may be greater by a factor of 3-fold.

Based on results from the latest WHO field study on human breast milk contaminant concentrations, average PCDD/PCDF levels, expressed on an I-TEQ basis, ranged from less than 10 pg/g milk fat in developing countries to 10-35 pg/g milk fat in industrialized countries. When dioxin-like PCBs are included, the total TEQ concentration increases in the order of 2-fold. For example, in a large sample of Dutch breast milk samples collected in 1990-91, the mean concentration of PCDD/PCDF TEQs was 34.4 pg/g milk fat; when dioxin-like PCBs were included in the calculation, the total TEQ value increased to 72.3 pg/g milk fat. The average daily intake of a breast- fed infant, on a body weight basis, therefore may be almost 1-2 orders of magnitude greater than that of an adult. It should be noted that the majority of industrialized countries have recorded decreases of up to 50% in the concentration of PCDDs/PCDFs and total PCBs in breast milk within the past.

When TEQ calculations (based on 1997 WHO TEFs) for exposure and body burden are considered on an individual congener basis in background populations TCDD generally accounts for only 10-20 % of the PCDD/PCDF-TEQs. When dioxin-like PCBs are also included TCDD often contributes less than 5 % to the total TEQ.10 years.

The consultation recommended that the new TEFs for PCDD/PCDF and dioxin-like PCB derived by WHO in 1997 (see Applicability of the TEF concept) should be used for future calculations of TEQs. This will result in an approximate 10% increase in TEQ calculations, compared to using I-TEFs and the initial 1994 WHO TEFs for PCBs.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 17-18

6.1.2 Toxicokinetics

The source document for this Digest states:

The key determinants in the kinetics and the half-lives of these compounds are amount of fat stores in the body, binding to CYP 1A2 in the liver, and rate of metabolism and excretion. The dose also plays a significant role and it was found that humans also sequester these compounds in the liver at higher doses, as do experimental animals. However, because of species variation in the above mentioned determinants, rodents require appreciably greater doses (100-200-fold) to reach the same equivalent body burdens as has been determined in humans exposed only to background concentrations to dioxin and related compounds. From a pharmacokinetic point of view, estimates of body burden are considered the most appropriate dosimetric parameter for interspecies comparison.

The existence of a relationship between average daily intake and resulting tissue levels in humans is supported by data from Germany which showed that decreases in average daily dioxin TEQ intake over the course of 7 years (1989-1996) were associated with similar declines in human milk and blood concentrations. Due to the relatively long half-lives in humans of dioxins and related compounds, steady-state body burden estimates usually reflect a stable condition in which brief intake above background will not result in significant changes to the body burden.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 18

6.2 Observed health effects

The source document for this Digest states:

Health effects

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.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 18-22

6.3 Tolerable Daily Intake set by WHO for dioxins

    • 6.3.1 How did WHO derive the intake limit?
    • 6.3.2 How must this limit be understood?

6.3.1 How did WHO derive the intake limit?

The source document for this Digest states:

Derivation of TDI

Estimation of a TDI for dioxin and related compounds would require that either a reliable No-Adverse-Effect-Level (NOAEL) or a reliable LOAEL be identified for the most sensitive (and relevant) adverse response, that can serve as a surrogate for all other adverse responses that might be expected from exposure to these compounds. The LOAELs for the most sensitive adverse responses reported in experimental animals (Table 4) were associated with body burdens from which a range of estimated long-term human daily intakes of 14-37 pg/kg/ day was calculated. The consultation noted that the lower and upper end of this estimated range was related to effects following acute gavage (bolus) exposure to rats, but that this range also included effects seen after dietary exposure of monkeys for a prolonged period of time (4 years), the latter more resembling the conditions of human intake of these compounds. In view of the uncertainties in establishing a single, most appropriate LOAEL for derivation of a TDI, the consultation concluded that the range of estimated human daily intakes of 14 - 37 pg/kg/day provided a reasonable basis for the evaluation of the health risk of dioxin-like compounds. In order to arrive at a TDI based on TEQs, the use of uncertainty factors also had to be addressed in order to allow: a) the use of a range of LOAELs instead of a NOAEL, b) the possible differences between humans and experimental animals in susceptibility to these compounds, c) the potential differences in susceptibilities within the human population, and d) differences in half-lives of elimination for the compounds of a complex TEQ mixture. Since body burdens have been used to scale doses across species, the use of an uncertainty factor to account for species differences in toxicokinetics is not required. With regards to the potential differences in susceptibility to the effects of these compounds, it is mentioned before that for some endpoints humans might be as sensitive as experimental animals to the adverse health effects of dioxin and related compounds. This implies that only a small uncertainty factor needs to be employed for differences in susceptibility. As the LOAELs presented in Table 4 were considered to be within a factor of 2-3 to the NOAELs, and the differences in half-lives between the dioxins and dioxin-like PCBs were also small (and partly accounted for in the establishment of the TEF values), the consultation was of the opinion that a composite uncertainty factor of 10 would be adequate.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 22-23

6.3.2 How must this limit be understood?

The source document for this Digest states:

The consultation emphasized, that the TDI represents a tolerable daily intake for life-time exposure and that occasional short-term excursions above the TDI would have no health consequences provided that the averaged intake over long periods is not exceeded. In addition, it recognized that certain subtle effects may be occurring in some sections of the general populations of industrialized countries at current intake levels (2-6 TEQ pg/kg bw/day) and body burdens (4-12 TEQ ng/kg bw), but found it tolerable on a provisional basis as these reported subtle effects were not considered overtly adverse and there were questions as to the contribution of non-dioxin-like compounds to the observed effects. The consultation therefore stressed that the upper range of the TDI of 4 pg TEQ/kg bw should be considered a maximal tolerable intake on a provisional basis and that the ultimate goal is to reduce human intake levels below 1 pg TEQ/kg bw/day.

The consultation therefore recommended that every effort should be made to limit environmental releases of dioxin and related compounds to the extent feasible in order to reduce their presence in the food chains, thereby resulting in continued reductions in human body burdens. In addition, immediate efforts should be made to specifically target exposure reductions towards more highly exposed sub-populations.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 23

6.4 Breastfeeding

The source document for this Digest states:

Breast-fed infants are exposed to higher intakes of these compounds on a body weight basis, although for a small proportion of their lifespan. However, the consultation noted that in studies of infants, breastfeeding was associated with beneficial effects, in spite of the contaminants present. The subtle effects noted in the studies were found to be associated with transplacental, rather than lactational, exposure. The consultation therefore reiterated conclusions of previous WHO meetings on the health significance of contamination of breast milk with dioxin-like compounds; namely that the current evidence does not support an alteration of WHO recommendations which promote and support breastfeeding. Based on new clinical data which supports the biological plausibility of certain experimental observations, continued and enhanced effort should be directed towards identifying and controlling sources of environmental input of these substances. The consultation noted that within the last 10 years there is clear evidence of a decrease in dioxin levels in human milk in almost every region for which suitable data exists. This is most probably attributable to enhanced identification and control of environmental input sources. A future consultation in approximately 5 years should evaluate progress towards these goals.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 23-24


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