Summary

The importance of axillary dissection as part of the primary surgical procedure in the treatment of operable cases of carcinoma of the breast is established. The morbidity of this procedure, however, is less well documented. A study of 126 women who had had full axillary dissection as part of their initial surgical treatment was undertaken to assess their degree of morbidity in terms of numbness, pain, weakness, swelling, and stiffness. Seventy per cent of cases complained of numbness, 33% of pain, 25% of weakness, 24% of limb swelling, and 15% of stiffness. Objective measurements confirmed decreased sensation in 81%, weakness in 27%, swelling in 10%, and stiffness in 10%. In no case were these symptoms described as severe, though they did have an effect upon the daily lives of 39%. The side effects of full axillary dissection are common and all women should be warned of them prior to surgery; however they are usually mild and therefore should not preclude this procedure as a part of definitive surgical treatment. Axillary dissection has a role in the management of early breast cancer as a major prognostic indicator (Fisher & Slack, 1970), as a guide to the need for adjuvant treatments It may not, however, influence overall survival rates and knowledge of the morbidity of the procedure is therefore important (Kissin et al. value of complete axillary dissection, as opposed to nodal sampling or partial dissections, is twofold. Firstly it reduces the risk of local axillary recurrence to less than 5%, lesser procedures carrying a proportionally higher risk of local recurrence, and secondly its predictive value, both of prognosis , and of the necessity for additional axillary radiotherapy, is greater. This study was performed to assess the morbidity following axillary dissection in terms of numbness, pain, weakness, swelling, and stiffness, both subjectively and objectively. Material and methods One hundred and twenty-six consecutive patients attending a Breast Clinic between December 1990 and April 1991 who fulfilled the following criteria were invited to participate in the study. (1) Had undergone full axillary dissection at six months previously. (2) Had not received radiotherapy to the axilla. (3) Had no evidence of locoregional or distant recurrence. (4) Had not received chemotherapy. Those who agreed to participate completed a questionnaire asking them to record current problems with pain, weakness, numbness, swelling, and stiffness in the treated arm. Those who complained of these were asked in each case; …

dioxin's toxicity has reignited controversy regarding safe exposure levels for dioxin and prompted the reassessment by the EPA. As part of these efforts, scientists at NIEHS developed mechanistic models to challenge the dioxin threshold hypothesis.
At the heart of the dioxin controversy is a proposed hypothesis that toxic effects of dioxin are receptor mediated, and at sufficiently low exposure to dioxin (i.e., a threshold), too few receptors would be occupied to produce a significant biological consequence. Researchers Christopher Portier and Michael Kohn of the Laboratory of Quantitative and Computational Biology, in collaboration with the Laboratory of Biochemical Risk Analysis and the Biostatistics Department of the German Cancer Research Center, used data on the effects of dioxin, including tissue concentrations, changes in expression of liver proteins, modification of plasma membrane epidermal growth factor, interactions with estrogens, cellular proliferation, and carcinogenesis, to create a comprehensive mechanistically based model of dioxin's effects.
Portier and Kohn found that although the classical receptor-mediated models theoretically allowed for both nonlinear behavior that mimics a threshold and linearity at low doses, these models failed to predict a nonlinear relationship at low doses. The models predict that binding of dioxin to the Ah receptor follows linear kinetics at low doses, and induction of the Ah receptor by the dioxin-Ah receptor complex does not alter this curvature. Binding of dioxin to other liver proteins does not seem to significantly affect the dose-response curve for expression of any of the proteins modeled. Not only were the NIEHS models unable to detect any nonlinearity in cell kinetics, they also indicated that dioxin potentially produces premalignant lesions in the liver.
Because changes in gene expression do not necessarily predict toxicity, current studies are attempting to develop dose-response models to determine if the toxic effects of dioxin exhibit linear or nonlinear behavior. For example, Portier and Kohn have undertaken a theoretical analysis of the impact of receptor-based models on the shape and magnitude of tumor incidence rates.

EPA Reevaluation of Dioxin's Risks
In 1991, then EPA administrator William Reilly initiated a reevaluation of dioxin's risks. George Lucier and Christopher Portier have been involved in this reevalua-Michael Kohn-modeling effects of dioxin tion in a number of ways. Lucier and Michael Gallo (EOHSI) co-chair the committee that prepared the dose-response models chapter, the cornerstone of the reevaluation. Portier played a key role in the development of biologically based dose-response models for dioxin's effects. Lucier also prepared the chapter on animal carcinogenicity. The dose-response models and animal carcinogenicity chapters received favorable reviews from the EPA Peer Review process in September 1992. The Scientific Advisory Board will review the background papers and the risk characterization in late 1993.

Species Differences in Butadiene Carcinogenesis
1,3-Butadiene, a gaseous hydrocarbon used in the production of synthetic rubber and other resins, is a carcinogen in rodents and is associated with leukemia and lymphoma in humans. Mice develop tumors at lower exposures to butadiene than rats. Recent studies have shown that mice have a higher capacity to oxidize butadiene to 1,2-epoxy-3-butene, a mutagenic and carcinogenic compound, than either rats or humans. Some investigators have concluded that species differences in tumor development are due to differences in metabolic activation of butadiene and detoxification of expoxide intermediates.
To validate this conclusion, two NIEHS scientists, Michael Kohn and Ronald Melnick, constructed physiologically based pharmacokinetic models of the distribution and clearance of inhaled butadiene in mice, rats, and humans. In contrast to the conclusions of earlier investigators, the models predict that species differences in the uptake of butadiene and the blood concentration of epoxybutene are much more sensitive to the physiological parameters (e.g., ventilation rate and cardiac output) than to the biochemical parameters.
In addition, the model predicts that, because of these physiological differences, butadiene accumulates in the fat of humans, but not mice, on repeated exposure. According to the model, butadiene released from fat during the periods between exposures continues to be converted into epoxybutene, adding to the carcinogenic risk. In a recent editorial in Science, it was stated that after exposure to 10 ppm butadiene in the ambient air, blood epoxybutene levels are 590 times higher in mice than in monkeys. Yet, in Kohn and Melnick's models, mice produce only 5.5 times as much epoxybutene as humans at exposures that result in equivalent amounts of butadiene absorbed into the body. Risk assessments of inhaled carcinogens are normally performed on the basis of internal dose rather than on the basis of atmospheric concentration. Inhalation studies can lead to different implications relevant to human risk depending on the manner in which the results are reported. Computed epoxybutene concentrations, by themselves, were found not to correlate with tumor incidence in mice and rats. Rats exposed to 1000 ppm butadiene generate about twice the concentration of epoxybutene in lung as mice exposed to 60 ppm. Yet mice develop lung tumors under those conditions and rats do not. Kohn and Melnick conclude that other biochemical processes (e.g., formation of DNA adducts, efficiency of DNA repair) not included in their models are more important determinants of the differential response of the two species than the concentration of the putative carcinogen.

Risk Assessment Seminar Series
As an adjunct to its initiatives in risk assessment, NIEHS is hosting a seminar series featuring prominent scientists in the risk assessment field. The first seminar was June 8, with Christopher Portier, chief of the NIEHS Laboratory of Quantitative and Computational Biology. Other speakers in the series will include David P. Rall, internationally recognized environmental health researcher and retired director of NIEHS; Joe Rodricks of Environ, a Washington, DC firm; John Graham of the Harvard Institute of Risk Assessment; William Farland and John Vandenberg of U.S. EPA; Henry Falk of CDC; Ellen Silbergeld of the University of Maryland at Baltimore and the Environmental Defense Fund; Leslie Staynor of NIOSH; Gil Omenn of the University of Washington; and Roger McClellan of the Chemical Industry Institute of Toxicology.
The series is designed to allow professionals in risk assessment to discuss critical issues. For information on the series contact George Lucier, (919) 541-3802. 394 Environmental Health Perspectives