Dioxins lethality

There is increasing interest in the relationship of the HS response to environmental toxicology. As induction of the HS response portends resistance to otherwise lethal stresses, many environmental hazards have the potential for inducing the HS response (Finnell et al., 1992). Activity of the dioxin receptor is affected by HS proteins (Nemoto et al., 1990 Pongratz et al., 1992) and it is likely that the HS... 

Acute Lethality. Samples of 2,7-dichlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, hexachlorodibenzo-p-dioxin, and octachloro-dibenzo-p-dioxin were evaluated for acute oral lethality in the following animals. 

Polychlorodibenzo- -dioxins Perinatal Effects and the Dominant Lethal Test in Wistar Rats... 

In male rats 2,3,7,8-tetrachlorodibenzo-p-dioxin induced hyperplastic changes and sperm granulomas in the epididymis, but no apparent lethal mutations were noted during post-meiotic phases of spermatogenesis. 

In the production of the herbicide 2,4,5-T (2,4,5 tetrachlorophenoxyacetic acid), a dioxin (2,3,7,8 tetrachlorodibenzodioxine) is often formed. Not only has it been called the second most lethal chemical ever discovered but it can also produce birth defects. During the early 1970s there were court battles over whether 2,4,5-T should be banned because of the possible presence of the dioxin. The Dow Chemical Company maintained that no detectable dioxin was produced in its process and that therefore its product was safe and should not be taken off the market. In this instance, the removal and hence concentration of the dioxin would pose problems of such a magnitude that the only feasible reaction conditions are the ones that produce no dioxin. 

For halogenated aromatic hydrocarbons like polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) the binding to the aryl hydrocarbon (Ah) receptor regulates their toxicity [89]. The Ah receptor controls the induction of one of the cytochrome P450 enzymes in the liver. Toxic responses such as thymic atrophy, iveight loss, immu-notoxicity and acute lethality are associated ivith the relative affinity of PCBs, PCDFs and PCDDs for the Ah receptor [89]. The quantitative structure-activity relationship (QSAR) models predicting the affinity of the halogenated aromatic hydrocarbons ivith the Ah receptor describe the electron acceptor capability as well as the hydrophobicity and polarizability of the chemicals [89[. 

Perhaps the most dramatic case of this is the acute toxicity of dioxins. At very low doses dioxins are lethal to guinea pigs, but they have only mild acute effects in humans (for a discussion of the resulting controversies around dioxins see Powell and Leiss, 1997, pp4l—76). 

Abbreviations. LD, lethal dose TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. Source Data from Loomis TA, Hayes AW. Loomis s Essentials of Toxicology. 4th ed. San Diego Academic Press, 1996. 

Sijm, T.H.M., Opperhuizen, A. (1988) Biotransformation, bioaccumulation and lethality of 2,8-dichlorodibenzo-p-dioxin a proposal to explain the biotic fate and toxicity of PCDD s and PCDF s. Chemosphere 17, 83-99. 

The wasting syndrome is a characteristic effect of exposure to 2,3,7,8-TCDD in animals and, in its most severe form, is usually associated with lethality, particularly in rodents. The fact that the wasting syndrome has not been demonstrated in humans does not necessarily indicate that humans are insensitive to this effect of dioxins, but may indicate that human exposure has not approached acutely high enough levels. 

Christian BJ, Inhom SL, Peterson RE. 1986a. Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 82 239-255. 

Khera KS, Ruddick JA. 1973. Polychlorodibenzo-p-dioxins Perinatal effects and the dominant lethal test in Wistar rats. Advances in Chemistry Series 12C 70-84. 

Pohjanvirta R, Unkila M, Tuomisto J. 1993a. Comparative acute lethality of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin in the most TCDD-susceptible and the most TCDD-resistant rat strain. Pharmacol Toxicol 73(l) 52-6. 

Rozman K. 1984. Separation of wasting syndrome and lethality caused by 2,3,7,8-tetrachloro-dibenzo-p-dioxin. Toxicol Lett 22 279-285. 

TCDD is the most toxic member of the 75 dioxins. It causes death in rats by hepatic cell necrosis. Death can follow a lethal dose by weeks. Acute and subacute exposure result in wasting, hepatic necrosis, thymic atrophy, hemorrhage, lymphoid depletion, chloracne. A by-product of the manufacture... 

Table 2. Lethal body burdens (LBB) in fish associated to different mechanisms of action, according to McKim and Schmieder [107], and extended with data for polychlorinated dibenzo-p-dioxins (PCDDs) [86,108], and organotin compounds [109,110] ...

TCDD, the most toxic of the 75 dioxin isomers and possibly the most toxic manufactured chemical, contaminates phenoxy herbicides during the production process (Demers and Perrin 1995 Klaassen 1985). Conflicting literature addresses TCDD lethality in humans. Some reviews deny that human deaths result from systemic effects of TCDD (Demers and Perrin 1995). Others describe successful suicides with phenoxy herbicides (Nielsen et al. 1965). Despite extensive reports of numerous medical conditions from TCDD, the literature confirms only chloracne and transient mild hepatotoxicity in humans. Table 1-6 lists the various, but unconfirmed, signs and symptoms associated with human poisonings. Table 1-7 lists the unconfirmed psychiatric symptoms attributed to TCDD exposure. 

Despite the attention paid to dioxin, these pollutants do not pose as acute a hazard as a large spill of a lethal gas (such as the Bhopal tragedy), or a burning disposal site. Rather, concern about dioxin focuses on long-term effects such as potential cancer formation or bloaccumulatlon In the food chain. Unlike many pollutants, PCDD are very Insoluble In water and are not as likely to leach Into groundwater as, for example, halogenated solvents. 

The comparative data on the acute lethality of the chlorinated dibenzo-p-dioxins and furans in laboratory animals are included in Table I. Evaluation of these data indicates that TCDD is the most toxic of this series. For the guinea pig, the single dose oral LD50 value is reported to be 0.6-2.0 yg/kg B.W., while in the hamster the single dose oral LD50 value is reported to be 1157-5051 yg/kg B.W. 

TCDD as the reference point, the extract caused only a slight degree of toxicity of the magnitude predicted for a dose level of 66 ng of 2,3,7,8-TCDD/kg BW/day. The severe toxicity and lethality predicted by the use of the TEF scheme to be associated with a composite dose level of 2000 ng of 2,3,7,8-TCDD TEF/kg BW/day was not observed in the rats. Thus, it appears as if the 2,3,7,8-TCDD TEF scheme (based on in vitro assays) for total chlorinated dioxins and furans substantiaTTy overpredicts the actual toxicity observed when in vivo studies of combinations of multiple dioxins and furans are conducted. 

Dibenzofuran, colourless, fluorescent crystals, mp 86°C, bp 287 C, occurs in coal tar. 2,3,7,8-Tetrachlorodibenzofuran and other polychlorodibenzofurans (abbreviated PCDFs) are extremely toxic and, like 2,3,7,8-tetrachlorodibenzo[l,4]dioxin (see p 371), belong to a group of compounds known as supertoxins [14]. The lethal dose for monkeys lies in the region of 0.07 mg/kg body weight. PCDFs are formed in traces during the industrial production of polychlorobenzenes, poly-chlorophenols and polychlorobiphenyls, as well as during the combustion or thermal decomposition of products which contain such compounds. Among these are pesticides, wood preserved with poly-chlorophenols, as well as transformer oils, e.g. ... 

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