Leukemia, lymphoma, and multiple myeloma after pelvic radiotherapy for benign disease.

The relationship between exposure to sparsely ionizing radiation and mortality due to cancers of hematopoietic and lymphopoietic tissues was studied among 12,955 women treated for benign gynecological disorders at any of 17 hospitals in New England or New York State and followed for an average of 25 years; 9770 women were treated by radiation (intracavitary 226Ra, external-beam X rays), while 3185 were treated by other methods, including curettage, surgery, and hormones. The average age at treatment was 46.5 years, and the mean dose to active bone marrow among irradiated women was 119 cGy. Forty deaths due to acute, myelocytic, or monocytic leukemia were observed among irradiated women. This number was 70% higher than expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.7; 90% confidence interval (CI) 1.3-2.3]. A deficit was recorded among nonirradiated women, based on three observed deaths (SMR = 0.5; 90% CI 0.1-1.2). A well-defined gradient in the SMR with dose among exposed women was not detected. The SMR was highest within 5 years after irradiation but remained elevated even after 30 years. The temporal pattern differed by subtype of leukemia: excess mortality due to chronic myelocytic leukemia occurred almost exclusively within the first 15 years, whereas the SMR for acute leukemia, though also elevated, varied little over time. Cancers of lymphoreticular tissue occurred more often than expected based on U.S. mortality rates, but not appreciably differently for irradiated and nonirradiated women. There was little or no evidence of effects attributable to radiotherapy for chronic lymphocytic leukemia [relative risk (RR) = 1.1; 90% CI 0.5-3.0], Hodgkin's disease (RR = 0.9; 90% CI 0.3-3.2), non-Hodgkin's lymphoma (RR = 0.9; 90% CI 0.6-1.6), or multiple myeloma (RR = 0.6; 90% CI 0.3-1.4). These results corroborate previous findings indicating that acute and myelocytic leukemias are the most prominent malignancies after exposure to sparsely ionizing radiation, occurring in excess shortly after irradiation, and that lymphomas are either not caused by radiation or are induced only rarely.

Cancer mortality following radium treatment for uterine bleeding.

Cancer mortality in relation to radiation dose was evaluated among 4153 women treated with intrauterine radium (226Ra) capsules for benign gynecologic bleeding disorders between 1925 and 1965. Average follow up was 26.5 years (maximum = 59.9 years). Overall, 2763 deaths were observed versus 2687 expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.03]. Deaths due to cancer, however, were increased (SMR = 1.30), especially cancers of organs close to the radiation source. For organs receiving greater than 5 Gy, excess mortality of 100 to 110% was noted for cancers of the uterus and bladder 10 or more years following irradiation, while a deficit was seen for cancer of the cervix, one of the few malignancies not previously shown to be caused by ionizing radiation. Part of the excess of uterine cancer, however, may have been due to the underlying gynecologic disorders being treated. Among cancers of organs receiving average or local doses of 1 to 4 Gy, excesses of 30 to 100% were found for leukemia and cancers of the colon and genital organs other than uterus; no excess was seen for rectal or bone cancer. Among organs typically receiving 0.1 to 0.3 Gy, a deficit was recorded for cancers of the liver, gall bladder, and bile ducts combined, death due to stomach cancer occurred at close to the expected rate, a 30% excess was noted for kidney cancer (based on eight deaths), and there was a 60% excess of pancreatic cancer among 10-year survivors, but little evidence of dose-response. Estimates of the excess relative risk per Gray were 0.006 for uterus, 0.4 for other genital organs, 0.5 for colon, 0.2 for bladder, and 1.9 for leukemia. Contrary to findings for other populations treated by pelvic irradiation, a deficit of breast cancer was not observed (SMR = 1.0). Dose to the ovaries (median, 2.3 Gy) may have been insufficient to protect against breast cancer. For organs receiving greater than 1 Gy, cancer mortality remained elevated for more than 30 years, supporting the notion that radiation damage persists for many years after exposure.

Leukemia following radiotherapy for uterine bleeding.

Mortality due to leukemia among 4483 women treated with radiation to control uterine bleeding between 1925 and 1965 was twice as high as expected based on U.S. population rates (standardized mortality ratio (SMR) = 2.0; 95% confidence interval (CI): 1.4 to 2.8). Women were followed for an average of 26.4 years. Relative risk was highest 2 to 5 years after treatment (SMR = 8.1) and among women over 55 years at irradiation (SMR = 5.8). The usual method of treatment was intrauterine radium. Average radiation dose to active bone marrow was estimated on the basis of original radiotherapy records (median, 53 cGy). A linear dose-response model provided an adequate fit to the data. The average excess relative risk was 1.9% per cGy (95% CI: 0.8 to 3.2), and the average absolute risk was 2.6 excess leukemia deaths per million women per year per cGy (95% CI: 0.9 to 4.8). Chronic myeloid leukemia predominated during the first 15 years following exposure, whereas acute leukemias and chronic lymphatic leukemia were most common thereafter. The radiation doses experienced during treatment of benign gynecologic disease appear to result in greater leukemia risk per cGy average marrow dose than the considerably higher doses used to treat malignant disease, perhaps because of a decreased likelihood of killing potentially leukemic cells.

Toxicity of vinyl chloride and poly(vinyl chloride): a critical review.

In 1974, vinyl chloride (VC) was first reported in the open scientific literature to induce angiosarcoma of the liver both in humans and in animals. Additional research has now demonstrated the carcinogenicity of VC to other organs and at lower concentrations. The target organs for VC now clearly include the liver, brain and the lung, and probably the lymphohematopoietic system. The evidence for a carcinogenic risk has been extended to jobs associated with poly(vinyl chloride) exposure. Cases of liver angiosarcoma have been reported among individuals employed in PVC fabrication facilities and an epidemiological study has demonstrated a significant association between exposure to PVC dust and the risk of lung cancer mortality. Cases of angiosarcoma of the liver also have been reported among individuals living in near proximity to vinyl chloride-poly(vinyl chloride) plants. An association between PVC dust and pneumoconiosis also has been demonstrated. On the basis of findings, prudent control of PVC dust in the industrial setting is indicated.

A modified life-table analysis system for cohort studies.

A person-years at risk life-table analysis system of computer programs has been developed by the National Institute for Occupational Safety and Health (NIOSH) and is available with detailed documentation. The system was specifically designed to analyze occupational cohort mortality data. These programs require more computer core space and processing time than other available life-table programs. However, the NIOSH programs are advantageous because they include the following: (1) input data editing and modification, (2) mortality rates for 89 cause-of-death categories, (3) assignment of cumulative doses to specific person-years based on either personal or area exposure data, and (4) simultaneous examination of observed and expected deaths by duration of employment (or dose), latency, age, and calendar time.

Toxicity of vinyl chloride and polyvinyl chloride as seen through epidemiologic observations.

In 1974, vinyl chloride (VC) was first reported in the scientific literature to induce angiosarcoma of the liver in animals and humans. Further research has now demonstrated the carcinogenicity of this agent to other organs. Target organs for VC now include the liver, brain, and lung, and probably the lymphohematopoietic system. The carcinogenic risk has been extended to jobs associated with polyvinyl chloride (PVC) exposure. This is evidenced by cases of liver angiosarcoma reported among individuals employed in or residing near PVC fabrication facilities and by epidemiologic study demonstrating a significant association between lung cancer and exposure to PVC dust. An association between PVC dust and pneumoconiosis has been demonstrated. On the basis of these findings, experimental bioassays and epidemiologic studies of the carcinogenicity of PVC are clearly in order. Prudent control of PVC in the industrial setting is also clearly indicated.

Epidemiology of asbestos-related diseases.

This paper is intended to give the reader an overview of the epidemiology of asbestos-related diseases and is restricted to primarily occupational exposure studies. However, some mention of nonoccupational exposures are made because of their direct relationship to a worker or to a secondary occupational source. Over 100 epidemiological studies are reviewed, dating back to the first case of asbestos-associated disease reported by Montague Murray in 1906. The studies are divided by specific fiber type and by specific disease outcomes and the interaction of asbestos and cigarette smoking is discussed in great detail.

A preliminary report of mortality patterns among foundry workers.

A proportional mortality study was conducted utilizing the death records maintained from 1971 to 1975 by the International Molders and Allied Workers Union as part of a death benefits program. Death certificates were obtained on 3,013 members of the study group and classified according to the 8th Revision of the ICA by a trained nosologist. The ate- and race-specific cause distribution of all deaths among males in the United States for 1973 were used as a standard from which expected deaths were calculated. The statistical significance of differences between observed and expected numbers of deaths was determined by a chi-square test. The most statistically significant finding in this study was an excess lung cancer mortality (208 observed vs. 142 expected) and an excess mortality due to pneumoconiosis (29 observed vs. 5 expected). A discussion is included of the potential agents found in the foundry environment that may be responsible for the increased lung cancer risk.

Leukaemia in benzene workers.

Workers occupationally exposed to benzene in 1940-49 were followed for vital status up to 1975. In comparison with two control populations, a significant (P less than 0-002) excess of leukaemia was observed. A five-old excessive risk of all leukaemias and a ten-fold excess of deaths from myeloid and monocytic leukaemias combined are demonstrated in the study population compared with controls. These figures under-estimate the true leukaemia risk to benzene-exposed workers, because follow-up is only 75% complete and the untraced 25% of the study population were all regarded, in the statistical analysis, as being alive at the end of the study period. The environment of the workers in the study population was not contaminated with solvents other than benzene, and existing records indicate that the benzene levels themselves were generally below the limits recommended at the time of their measurement.

Carcinogenic, mutagenic and teratogenic risks associated with vinyl chloride.

The data presented demonstrate clearly that vinyl chloride (VC) is related to a significant excess of mortality from cancer of the liver, lung and brain among workers occupationally exposed to VC. The risk of dying from cancer of the lymphatic and hematopoietic system also appears to increase with an increase in latency. These cancer sites could have been predicted by the animal bioassay conducted by Maltoni. With regard to the liver, even the histophthologic type of cancer (angiosarcoma) was observed first in experimental animals. A study of cancer mortality among populations residing proximate to VC polymerization facilities also demonstrated an increased risk of dying from CNS and lymphatic cancer. These latter findings raise cause for concern about out-plant emmissions of VC, but without further study these cancers obviously cannot be interpreted as being related to out-plant exposure to VC. Various test systems now have elicited a positive mutagenic response to VC. Thus, our observations of a significant excess of fetal mortality among the wives of males, who were occupationally exposed to VC, raise public health concern that VC may be mutagenic in humans. With regard to the teratogenicity of VC, observations of a significant excess of children born with birth defects were reported among populations residing proximate to VC polymerization facilities. Additional epidemiologic study is needed to determine whether a repeated pattern of excessive numbers of children born with birth defects can be observed in other communities with VC polymerization facilities.

Genetic risks of vinyl chloride.

A study of pregnancy outcome among wives of workers exposed to vinyl-chloride monomer (V.C.M.) indicated that, in comparison with controls, there was a significant excess fetal loss in the group whose husbands had a primary exposure to V.C.M., whereas no differences between the groups were observed before the husband's exposures. The difference in fetal death-rates for the post-exposure comparisons was a reflection of a greater fetal loss associated with the wives younger-aged husbands. The significant excess did not seem to be the result of bias from interviewers, respondents, nor from women who had experienced chronic abortions weighting the results. These findings, in conjunction with the demonstration of a mutagenic response via microbial test systems and with observations of significant excesses of chromosomal aberrations among workers exposed to V.C.M., raise scientific and public-health concern for the possible genetic risks of V.C.M. to man.