Veterans at Risk The Health Effects of Mustard Gas and Lewisite (1993) / Chapter Skim
Currently Skimming:
6 Relationship of Mustard Agent and Lewisite Exposure to Carcinogenesis
6 Relationship of Mustard Agent and Lewisite Exposure to Carcinogenesis
Pages 81-111
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 81... ...
Human epidemiologic information about the carcinogenicity of war gas comes from epidemiologic studies of workers exposed in its manufacture, soldiers exposed on the battlefield, and patients exposed to the agents when used for therapeutic purpose~ironically, usually to fight cancer. In considering the potential carcinogenicity of a chemical, it is 81
|
From page 82... ...
Because the various sulfur mustards are known to be animal carcinogens, much of this concern has centered around their potential carcinogenicity to humans. One part of the process of assessing the carcinogenic risk involves examination of the biologic fate of this compound, its potential genotoxicity, and its ability to induce mutations in living systems.
|
From page 83... ...
In addition, the repair of DNA lesions induced by sulfur mustards has been studied in many systems, including those employing cells known to be naturally deficient in certain repair enzymes (Ball and Roberts, 1970; Fox and Fox, 1973; Gilbert et al., 1975; Lawley and Brookes, 1968; Murnane and Byfield, 1981; Plant and Roberts, 1971; Reid and Walker, 1966, 1969; Roberts and Kotsaki-Kovatsi, 1986; Roberts et al., 1986; Savage and Breckon, 1981; Walker, 1966; Walker and Reid, 1971; WaLker and Smith, 1969~. As expected, DNA repair-deficient cells generally are much more sensitive to the DNA cross-linking, and the cells die at significantly lower doses.
|
From page 84... ...
Therefore, the 0-6 aLkyl product in DNA may be the major mutagenic lesion produced by the sulfur mustards. Cytogenetic and Mutagenic Effects Sulfur mustard induces chromosome aberrations—gross structure breaks visible under light in a variety of cell systems.
|
From page 85... ...
The sulfur mustards are genotoxic in a wide variety of cells, producing chromosome aberrations and gene mutations in vitro in a dose-related fashion. They also induce SCE and hart mutations in vivo in the peripheral blood lymphocytes of individuals exposed at low doses.
|
From page 86... ...
in mouse cells in culture (Barrett et al., 1989; Lee et al., 1988~. Arsenic exposure in vivo also has been reported to induce chromosome aberrations in human lymphocytes (Nordenson et al., 1978~.
|
From page 87... ...
Arsenite synergistically enhances the clastogenic action of alkylating agents, perhaps through binding to DNA repair proteins. EVIDENCE OF LONG-TERM HEALTH EFFECTS Animal Studies This section reviews the results of the published experimental carcinogenesis studies of sulfur mustard and nitrogen mustard.
|
From page 88... ...
. Early Studies in Mice and Rats One of the earliest reports of the carcinogenic effect of the nitrogen mustards is an interim report describing preliminary results on the intravenous, intraperitoneal, and subcutaneous injections of H N2 and HN3 into Swiss mice and albino rats (Griffin et al., 1950~.
|
From page 89... ...
E Heston and his colleagues conducted a series of studies in which sulfur mustard and nitrogen mustard were administered to strain A mice and the occurrence of pulmonary tumors was studied (Heston, 1949, 1950, 1953a,b; Heston et al., 1953~.
|
From page 90... ...
of Expenment Duration Mice Nodules Nodules Nitrogen mustard Experiment I: two to four intravenous injections of 1 mg/kg HN2 (14 received 4 injections; 22 received 3; and one, 2) at 2-day intervals 1~16 wks 29 100 3.48 Control 1~16 wks 30 13 0.17 Experiment II: Four intravenous ~njechons of 1 mg/kg HN2 at 2-day intervals 10 mos 20 100 9.60 Control 10 mos 32 63 0.81 Experiment III: One intravenous injector of 4 mg/kg HN2 10 mos 9 100 7.56 Control 10 mos 31 58 0.94 Sulfur mustard Experiment IV: Four intravenous injections of 0.65 mg/kg at 2-day intervals 16 wks 15 93 2.60 Control 16 wks 28 61 0.93 Experiment V: Four intravenous injections of 0.65 mglkg at 2-day intervals 16 wks 47 69 1.09 Control 16 wks 46 13 0.13 SOURCE: Heston, 1949, 1950.
|
From page 91... ...
Of the tumors at sites other than the site of injection, only pulmonary nodules from HN2 injections were significantly different from control animals: 34 of 73 injected animals developed pulmonary tumors, compared with 14 of 74 control animals. For all C3H and C3Hf animals, tumors appeared in 8.4 percent injected with sulfur mustard, compared with 15.8 percent of controls.
|
From page 92... ...
7 10.6 1 Papilloma - - ~ 1 Squamous cell carcinoma 8.6 1 Papilloma 2 Pulmonary tumors 7 Mammary tumors 8 Pulmonary tumors 9 Hepatoma 2 Liver F 8 M (24)
|
From page 93... ...
Later Studies of Mustard Agents and Other Alkylating Agents Several studies conducted at Edgewood Arsenal examined the toxic and carcinogenic effects on rats of chamber (whole body) exposure to sulfur mustard (McNamara et al., 1975~.
|
From page 94... ...
Each assay consisted of 12 thrice-weekly intraperitoneal injections of the various compounds; at least four dose levels were used for each compound and follow-up continued for 39 weeks. Although negative results were obtained for many compounds, a strong positive effect was seen with nitrogen mustard: total doses of HN2 between 0.02 and 17.5 ,uM/kg produced pulmonary tumors in 30 to 95 percent of the experimental animals.
|
From page 95... ...
. "Skin, basal cell carcinoma (agent related)
|
From page 96... ...
A 15-minute~inhalation exposure to a very high but unknown vapor concentration of sulfur mustard produced a marginally significant increase of pulmonary tumors, again in strain A mice. Sprague-DawleyWistar rats developed a substantial increase in skin malignancies from long-term chamber exposure to 0.1 mg/m3 of sulfur mustard.
|
From page 97... ...
Subcutaneous exposures produced injection site tumors and pulmonary tumors in selected strains of mice. Its tumorigenic potency appeared to be similar to or somewhat greater than sulfur mustard; HN2 was one of the most potent aLlcylating agents tested in the strain A bioassay program.
|
From page 98... ...
First, it indicates, albeit indirectly, that workers in the two groups with lung cancer excess (cohorts 1 and 2) were not exposed to phosgene; phosgene-exposed workers appear to be included in cohort 3, "the production of other gases." Secondly, this paper reports 11 cases of cancer of the larynx among the 674 workers exposed to sulfur mustard and only 1 case among the group not exposed to sulfur mustard.
|
From page 99... ...
However, none of these potential methodologic problems are likely to explain the extraordinarily elevated mortality ratio for cancer of the respiratory tract or the unusual anatomical distribution of malignancies. Taken as a whole, this paper provides substantial evidence that occupational exposure to sulfur mustard is associated with cancer.
|
From page 100... ...
Examination of cancer incidence, rather than cancer mortality, provides a parapet conclusion: 7 workers developed cancer of the larynx, compared with 0.75 expected, yielding a relative risk of 9.3. The relative risk for lung cancer was elevated, albeit not significantly, compared to the general population of England and Wales (21 observed versus 13.43 expected; relative risk equal to 1.6)
|
From page 101... ...
The study nevertheless reveals a possible etiologic association between mustard agent burns and aggressive basal cell carcinoma.
|
From page 102... ...
However, ANL was also found to occur in other types of cancer patients who had been treated with nitrogen mustards and other alkylating agents (Einhorn, 1978; Fisher et al., 1985; Greene et al., 1982~. In particular, patients with ovarian cancer treated with melphalan and chlorambucil developed this complication.
|
From page 103... ...
However, because sulfur mustards and nitrogen mustards have similar effects on DNA, the clinical experience with nitrogen mustards supports the evidence that sulfur mustard is carcinogenic in man. SUMMARY Gaps in the Literature There are three major gaps in the epidemiologic literature on occupational exposure.
|
From page 104... ...
It produced skin malignancies in chamber exposure in rats. Intravenous injection produced a significant increase in pulmonary tumors in highly susceptible strain A mice.
|
From page 105... ...
Subcutaneous exposures produced injection site tumors and pulmonary tumors in selected strains of mice. Its carcinogenic potency appeared to be similar to sulfur mustard, and it was one of the most potent carcinogens amongst the alkylating agents tested in the strain A bioassay program.
|
From page 106... ...
1955. Mustard gas poisoning, chronic bronchitis, and lung cancer: an investigation into the possibility that poisoning by mustard gas in the 1914-1918 war might be a factor in the production of neoplasia.
|
From page 107... ...
1978. Multiple Bowen's disease observed in former workers of a poison gas factory in Japan with special reference to mustard gas exposure.
|
From page 108... ...
1981. Cancer of the larynx and other occupational hazards of mustard gas workers.
|
From page 109... ...
1988. Epidemiological studies of lung cancer in Japanese mustard gas workers.
|
From page 110... ...
1971. Evidence for the inactivation and repair of the mammalian DNA template after alkylation by mustard gas and half mustard gas.
|
From page 111... ...
1963. On the late injuries following occupational inhalation of mustard gas, with special references to carcinoma of the respiratory tract.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.