Chlorine, estrogenicity

Montforts et further explored this approach by attaching hydrophilic carbohydrate structural units to certain chlorins (e.g., 406). Such conjugation increased the water solubility of the parent chlorins 407 and 408. By introducing an estradiol with a diethyl spacer, the chlorin-estrogen conjugate was then prepared in the hope that it would bind to an estrogen receptor which could induce selective destruction of mammalian carcinoma (Scheme 82). 

Hu J, S Cheng, T Aizawa, Y Terao, S Kunikane (2003) Products of aqueous chlorination of 17[5-estradiol and their estrogenic activities. Environ Sci Technol 37 5665-5670. 

Bakke et al. (1982) have shown how montmorillonite catalyses chlorination and nitration of toluene nitration leads to 56 % para and 41 % ortho derivative compared to approximately 40 % para and 60 % ortho derivatives in the absence of the catalyst. Montmorillonite clays have an acidity comparable to nitric acid / sulphuric acid mixtures and the use of iron-exchanged material (Clayfen) gives a remarkable improvement in the para, ortho ratio in the nitration of phenols. The nitration of estrones, which is relevant in making various estrogenic drugs, can be improved in a remarkable way by using molecular engineered layer structures (MELS), while a reduction in the cost by a factor of six has been indicated. With a Clayfen type catalyst, it seems possible to manipulate the para, ortho ratio drastically for a variety of substrates and this should be useful in the manufacture of fine chemicals. In principle, such catalysts may approach biomimetic chemistry our ability to predict selectivity is very limited. 

The ability of surfactants to induce cell proliferation in in vitro and in vivo tests has been demonstrated for APs, some lineal alcohols and bisphenols. In contrast, APEO, LAS, SPCs, AG and APGs are devoid of estrogenic activity. In addition, it has been demonstrated that low chlorination of APs or low bromination of bisphenols does not affect estrogenicity but may affect the biodistribution of the resulting chemicals. It is proposed that surfactants in current use and new chemicals under development should be carefully tested for estrogenic activity. 

Kupfer D. 1982. Studies on short and long-range estrogenic action of chlorinated hydrocarbon pesticides. In Hunt VR, Smith MK, Worth D, eds. Environmental factors in human growth and development. Banbury Report No. 1 1, Cold Spring Harbor Laboratory, 379-393. 

Hu J-y, Aizawa T, Ookubo S (2002) Products of aqueous chlorination of bisphenol A and their estrogenic activity. Environ Sci Technol 36 1980-1987... 

As reviewed by Fereira et al. [104], the reaction of estrogens, that is estrone, estradiol, and ethinylestradiol, with free chlorine occurs mainly via an electrophilic substitution at the ortho and para positions, which results eventually in cleavage of the aromatic structure. Several authors have reported that dichlorinated derivatives present less estrogenic activity than monochlorinated derivatives, and in most cases, estrogen DBFs are less potent in terms of estrogenicity than the parent compounds. 

At that time (1994-96), I had research support for a project on estrogenic compounds funded by the Chemical Manufacturers Association (CMA) my only official contact with the association was Ann Mason, Director of Scientific and Regulatory Affairs (Chlorine Chemistry Council, CMA), who asked for a yearly report. My opinions on the endocrine disruptor hypothesis have been based on analysis of scientific publications and have been consistent prior to, during, and after the research (not personal) support from the CMA. 

Among the known sequelae of exposure to chlorinated organics in mammals is that of estrogen-like activity (ref. 8 ). DDT inhibition of testicular growth and secondary sex characteristics development in white... 

Variations in the use pattern of industrial and agricultural chemicals throughout the world preclude standardization by international organizations such as OECD. Despite this fact, common dietary constituents, which are known to influence toxicity are antioxidants, unsaturated fatty acids, and selenium. These must be present in interfering concentrations. The potential impact of several common dietary contaminants on chronic toxicity assessment therefore, necessitates that special attention be given to their presence. In this respect, substances of concern include pesticide residues, chlorinated and polycyclic aromatic hydrocarbons, estrogens, heavy metals, nitrosamines, and mycotoxins. 

Current concerns with estrogenic compounds and their influence on a broad range of reproductive disorders, along with possible carcinogenic effects, have renewed interest in chlorinated pesticides. The need for ongoing scientific research to assess the potential risk posed by these compounds seems inevitable. 

It is also known that Toxaphene has low estrogenic activity. However, it is not clear which compounds of the mixture are responsible for this effect. With the pure single chlorinated bornane congeners this is now also possible. It is assumed that some hydroxylated chlorinated bornane metabolites and/or keto metabolites may be responsible for the estrogenic activity. 

Wfe have recently carried out experiments with cell-based and animal models of inflammatory diseases. The experiments have revealed that human polymorphonuclear cells once activated with phorbol esters to cause an inflammatory response produce copious amounts of chlorinated polyphenol species. Rats treated with lipopolysaccharide (LPS) in an in vivo model of inflammatory disease heavily nitrate polyphenols in tissues (e.g., lung and liver) where inflammatory cell invasion occurs. These modified polyphenols are better antioxidants than their parent compound. Using a luciferase reporter gene assay in COS cells, both chloro- and nitrogenistein were shown to have 1-2 orders lower estrogen receptor activation than genistein itself. In summary, metabolism of polyphenols is rampant, but not always inactivating. 

Aroclor 5442 was eight times more estrogenically active in rats than some low chlorinated PCBs, whereas highly chlorinated PCBs and PCTs were inactive [51]. The reproductive effect of PCTs has only been studied in the laboratory. A greater number of abnormal white leghorn chicken embryos was noted after a 20 mg/kg diet of Aroclor 5460 [56]. The hatchability was not effected, even after a 20 mg/kg diet of Aroclor 5442 [57]. 

---