University of Pittsburgh, Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261
Sid Laskin was from Brooklyn, and it was a statistical certainty that anyone who was with him for more than a few minutes would be told about his Brooklyn background. To Sid, these roots provided guidance in his professional career. A characteristic that he ascribed to his background, for example, was the ability to go right to the heart of an issue, to ignore peripheral distractions. He delighted in finding simple fixes to complex issues. This was evident in his choice of problems, in his experimental design, and in his technical approaches. He also was a stubborn man, stubborn in his insistence on the highest quality of work and on the highest ethical standards. There are various explanations as to why he never made the minor revisions needed to get his PhD thesis accepted at the University of Rochester. But they are all consistent with his stubborn insistence on the highest scientific standards in the performance and presentation of his work.
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After receiving his bachelors degree from Brooklyn College in 1940, Laskin stayed at the school on a biology fellowship for two years before being caught up in the war effort; he worked first at Cold Springs Harbor Laboratory and then as a member of the Manhattan Project assigned to the University of Rochester where, postwar, he became Chief of the Aerosol Unit of the Atomic Energy Commission Project. In 1951 he joined the Institute of Environmental Medicine of New York University Medical Center, where he spent the rest of his career.
Laskins studies on the role of particle size in relation to toxicity exemplify his phenomenal technical skills and his ability to bring his knowledge of physics to solve toxicological problems. With Herbert Stokinger, one of the great leaders in the field of toxicology, Laskin wrote a seminal paper in 1950 on Air Pollution and the Particle Size Toxicity Problem (Stokinger and Laskin, 1950). Thereafter, he and his colleagues continued to write papers demonstrating the centrality of particle size to lung toxicity. Their approach showed a precocious understanding of the many issues that are crucial today to understanding the health impacts of fine particles. Unfortunately, this was not taken into account in the initial regulatory standards for particulates, which were based solely on the total mass weight (total suspended particulates, or TSP). The result was that air pollution control technology focused on removing larger, heavier particles, thereby decreasing total airborne particle weight but having negligible impact on adverse health effects.
The studies with Stokinger also examined the acute toxicity of inhaled beryllium (Hall et al., 1950). Laskin contributed to this work by correlating toxicity with the physical chemical properties of beryllium oxide dust.
Laskins experimental designs to investigate the particulate problem were straightforward and elegant in their simplicity. The work could not have proceeded without his superb technical proficiency for inventing and validating devices that could generate and measure particles of different size, and deliver these particles to experimental animals.
One of his first papers at the University of Rochester concerns development of a technique to aerosolize penicillin solutions (Bryson et al., 1944). There was an extreme shortage of this new antibiotic during World War II. The ability to directly nebulize penicillin in relatively small amounts was thought to be likely to extend its availability to even more patients suffering from diseases readily curable by this wonder drug. This early study clearly foreshadows the characteristics that Laskin brought to inhalation toxicology. It was done with relatively low-tech methodology, was readily replicable elsewhere, and was based upon studies in laboratory animalsin this case rabbits. Particular attention was paid to the importance of particle size that was measured; the work was extended in vivo into determination of whether penicillin had penetrated into the blood system, and the study was validated in humans by determining the percentage of penicillin received by aerosol that was actually excreted in the urine.
Laskin was also one of the coauthors of a series of studies that demonstrated that the particle size of uranium dioxide dust was crucial in determining its toxicity (Wilson et al., 1948, 1952
, 1955
). From rereading these papers, it is clear that more than fifty years ago, Laskin and his colleagues had already demonstrated that fine particles were especially toxic. In the studies with uranium dioxide, dust of mass medium particle diameter of 0.45 micron was shown to be more toxic when inhaled by rabbits and rats than uranium dioxide dust at the same mass concentration but at a mass medium particle diameter greater than 1 µ. To do this study, Laskin and colleagues needed to demonstrate the satisfactory application of the modified cascade impactor as an instrument for following changes in particle size distribution, and they needed to solve the problem of providing a dry aerosol in the exposure chamber when starting with aqueous emulsions. They also developed a technique to start with concentrated suspensions of particles, yet prepared two different particle size ranges.
Laskins early work was supported by the Atomic Energy Commission and was based upon the need to understand the potential occupational problems for people in the nascent nuclear industry and those involved in nuclear weapons production. Experiments with different means of applying a carcinogenic compound to the bronchial mucosa of animals led to development of the intrabronchial pellet implantation technique, which was particularly suitable for extrapolating radiation dose to experimental carcinogenesis. Among Laskins key studies was production of carcinoma of the lung in rats exposed to beta-radiation from intrabronchial ruthenium106 pellets (Laskin et al., 1963).
Laskins interests were exceptionally broad. He was the inventor of a number of very important systems used for for inhalation toxicology studies (Drew et al., 1978; Laskin and Drew, 1970
); these inventions ranged from an inexpensive portable inhalation chamber to dust generation and air sampling systems (Drew and Laskin, 1971
; Leach et al., 1953
; Lippmann et al., 1967
; Spiegl et al., 1953
). His approach was notable for the simple elegance of the designs. Laskin did not depend upon highly complex technology, but instead used straightforward design with relatively inexpensive equipment generally available to other investigators. This minimized the potential for mechanical problems and increased the likelihood that there was more than a chance relation between estimated and actual dose to the laboratory animal. The Laskin Aerosol Generator is still in use today.
One of the most productive collaborations in experimental carcinogenesis was that between Laskin and Marvin Kuschner. Their seminal studies on inhalation carcinogenesis were characterized by eminently practical approaches to developing theoretical models of lung cancer, permitting the testing of hypotheses concerning the mechanisms by which inhaled agents led to the production of lung cancer. Laskin and Kuschner were leaders at a time of rapid growth and understanding of the basic processes by which chemicals produce cancer in vivo. With their colleagues at New York University, particularly within the Institute of Environmental Medicine under the leadership of Dr. Norton Nelson, they first developed many of the basic concepts of chemical/biological interactions leading to lung cancer.
With Kuschner, Laskin wrote an important conceptual article that discussed experimental models for environmental carcinogenesis and assessed the different approaches to studying laboratory animal cancer and the relevance of these approaches to humans (Kuschner and Laskin, 1971). They were particularly interested in understanding dose response relationships. Both were members of a distinguished group who reviewed the topic of lung cancer for IARC in 1976 (Pour et al., 1976
).
Among Laskins key contributions were studies of the inhalation carcinogenicity of haloethers. Following the epidemiological finding of lung cancer in chloromethyl methyl ether (CMME) workers, Laskin and colleagues, including Kuschner, Nelson, and Robert Drew, performed experimental studies that demonstrated CMME also produced malignant lung tumors in exposed rats and in exposed hamsters (Drew et al., 1975; Laskin et al., 1975
). Again with Laskin in the leadthis time joined by, among others, Kuschner, Nelson, Arthur Sellakumar, George Rusch, Gary Katz, and Roy Albertthe researchers demonstrated that inhalation exposure to epichlorohydrin, a bifunctional alkylating agent, produced squamous carcinoma of the nasal tract (Laskin et al., 1980
). This study was consistent with other work done at the New York University Institute of Environmental Medicine that suggested the importance of dose rate in chemical carcinogenesis. Laskin was also the senior author in a paper examining organ culture of rat trachea as a test system for studying carcinogenesis (Palekar et al., 1968
). This very early approach to what is now fairly routine toxicological method again demonstrates Laskins willingness to move beyond his own field of inhalation toxicology to provide the techniques necessary to answer questions pertinent to understanding carcinogenesis.
Laskins expertise in inhalation exposure was particularly important to the study of the mixture of gaseous formaldehyde and hydrogen chloride in the induction of nasal cancer in rats (Laskin et al., 1971). Bischloromethyl ether (BCME) is a highly reactive industrial alkylating agent that was shown to be carcinogenic in mice by skin painting, and highly carcinogenic in the respiratory tract of rats by inhalation. An epidemiological study of exposed workers subsequently showed BCME to be carcinogenic in humans. The NYU investigators noted that BCME broke down to hydrochloric acid and formaldehyde, and that a mixture of these two compounds would produce a gas phase reaction that resulted in low levels of BCME. This led them to do combined exposure studies, which had the important outcome of confirming the Chemical Industry Institute of Toxicology findings that formaldehyde alone produced a carcinogenic response (Albert et al., 1982
).
Laskins studies, along with those of his colleagues, were a very important link in demonstrating the overall soundness of toxicology as an approach to experimental carcinogenesis. The NYU Institute of Environmental Medicine had a range of investigators who made profound advances in understanding experimental carcinogenesis. Of note were the studies of Dr. Benjamin Van Duuren, an organic chemist whose knowledge of chemical reactivity was particularly important in developing an understanding of the inherent structure aspects of chemical carcinogenesis (Van Duuren, 1977). He tested his theoretical approaches using models of skin cancer. Van Duurens simple models were validated by the inhalation toxicology program developed by Laskin. By showing that compounds such as BCME and epichlorohydrin produced not only skin cancer but also lung cancer in animal models, they provided a very necessary scientific confirmation of the value of animal toxicology as a predictor of human cancer.
I was fortunate to work closely with Laskin from 1975 until his death. He was Principal Investigator, and I was co-investigator, of a comprehensive study of benzene toxicology funded by the American Petroleum Institute at the Sterling Forest site of the NYU Institute of Environmental Medicine. This was my first introduction to working with a broadly-based multi-disciplinary scientific group. I naively believed that this work was being done worldwide, but in fact, it has been very difficult for any of us to reproduce the breadth of approach used by Laskin and colleagues. The benzene studies ranged from long-range inhalation studies on end points of hematological toxicity and cancer (Goldstein et al., 1982; Snyder et al., 1978
, 1980
, 1982
, 1984
); methodological approaches to determining benzene in tissue and in blood (Snyder et al., 1975
, 1977
); evaluation of benzene toxicity in the fetus (Green et al., 1978
); toxicokinetic evaluation of benzene metabolism (Rusch et al., 1977
; Snyder et al., 1981
), and a synthesis and overview of the entire subject published as a journal supplement (Laskin and Goldstein, 1977
). As our review of literature and our command of the subject improved, it became more and more evident that benzene was unquestionably a human leukemogen. I recall sitting down with Laskin within a few months of becoming involved with these studies and telling him that in my first look at the literature as a hematologist, it was reasonably certain that benzene was a cause of human leukemia. Before I could say anything further, he immediately insisted that we should write it as we saw it and not be concerned about the fact that industry was providing the funding. Our review clearly stated that benzene caused human leukemia, and at the time, it was highly instrumental in convincing the petroleum industry and others that the problem was real.
The death of Sidney Laskin was a shock to us all. He died a young man with many years of significant contributions to inhalation science and to experimental carcinogenesis unrealized. He left behind a superb legacy of innovative science and of well-trained scientists who themselves have become leaders in the field. His legacy to toxicology also extends to two of his three children, who have themselves become outstanding toxicological scientists: Dr. Debra Laskin of Rutgers University and Dr. Jeffrey Laskin of Robert Wood Johnson Medical School, both members of the Environmental and Occupational Health Sciences Institute in New Jersey.
ACKNOWLEDGMENTS
Among the many former colleagues of Sid Laskin who contributed their recollections to this manuscript, I am particularly indebted to Dr. Robert Drew, whose careful reading led to correction of a number of technical errors as well as to improvement of the presentation. My deep thanks also to Drs. Debra Laskin and Jeffrey Laskin for their information and loving insight. And Sid would not permit me to write anything about him without emphasizing the importance of his wife, Laura Laskin, to all of his accomplishments.
NOTES
1 To whom correspondence should be addressed. Fax: (412) 624-3309. E-mail: bdgold{at}pitt.edu.
REFERENCES
Albert, R. E., Sellakumar, A. R., Laskin, S., Kuschner, M., Nelson, N., and Snyder, C. A. (1982). Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat. J. Natl. Cancer Inst. 68, 597603.[ISI][Medline]
Bryson, V., Sansome, E., and Laskin, S. (1944). Special Articles: Aerosolization of penicillin solutions. Science 100, 3335.
Drew, R. T., Bernstein, D. M., and Laskin, S. (1978). The Laskin aerosol generator. J. Toxicol. Environ. Health 4, 661670.[ISI][Medline]
Drew, R. T., and Laskin, S. (1971). A new dust generating system for inhalation studies. Am. Ind. Hyg. Assoc. J. 32, 327330.[ISI][Medline]
Drew, R. T., Laskin, S., Kuschner, M., and Nelson, N. (1975). Inhalation carcinogenicity of alpha halo ethers: I. The acute inhalation toxicity of Chloromethyl Methyl Ether and Bis (Chloromethyl) Ether. Arch. Environ. Health 30, 6169.[ISI][Medline]
Goldstein, B. D., Snyder, C. A., Laskin, S., Bloomberg, I., Albert, R. E., and Nelson, N. (1982). Myelogenous leukemia in rodents inhaling benzene. Toxicol. Lett. 13, 169173.[CrossRef][ISI][Medline]
Green, J. D., Leong, B. K., and Laskin, S. (1978). Inhaled benzene fetotoxicity in rats. Toxicol. Appl. Pharmacol. 46, 918.[ISI][Medline]
Hall, R. H., Scott, J. K., Laskin, S., Stroud, C. A., and Stokinger, H. E. (1950). Acute toxicity of inhaled beryllium: III. Observations correlating with the physicochemical properties of beryllium oxide dust. Arch. Ind. Hyg. Occ. Med. 2, 2548.[ISI]
Kuschner, M., and Laskin, S. (1971). Experimental models in environmental carcinogenesis. Am. J. Pathol. 64, 183191.[ISI][Medline]
Laskin, S., and Drew, R. T. (1970). An inexpensive portable inhalation chamber. Am. Ind. Hyg. Assoc. J. 31, 645646.[ISI][Medline]
Laskin, S., Drew, R. T., Cappiello, V., Marvin, K., and Nelson, N. (1975). Inhalational carcinogenicity of alpha halo ethers: II. Chronic inhalation studies with chloromethyl methyl ether. Arch. Environ. Health 30, 7072.[ISI][Medline]
Laskin, S., and Goldstein, B. D. (1977). Benzene toxicity: a critical evaluation. Toxicol. Environ. Health 2(Suppl.).
Laskin, S., Kuschner, M., Drew, R. T., Cappiello, V. P., and Nelson, N. (1971). Tumors of the respiratory tract induced by inhalation of bis (chloromethyl) ether. Arch. Environ. Health 23, 135136.[ISI][Medline]
Laskin, S., Kuschner, M., Norton, N., Altshuler, B., Harley, J. H., and Daniels, M. (1963). Carcinoma of the lung in rats exposed to the &exists;-radiation of intrabronchial ruthenium106 pellets. I. Dose-response relationships. J. Natl. Cancer Inst. 31, 219226.[ISI][Medline]
Laskin, S., Sellakumar, A. R., Kuschner, M., Nelson, N., Mendola, S. L., Rusch, G. M., Katz, G. V., Dulak, N. C., and Albert, R. E. (1980). Inhalation carcinogenicity of epichlorohydrin in noninbred sprague-dawley rats. J. Natl. Cancer Inst. 65, 751757.[ISI][Medline]
Leach, L. J., Wilson, R. H., Lauterbach, K. E., Spiegl, C. J., and Laskin, S. (1953). Semiportable air-sampling system. Arch. Ind. Hyg. Occup. Med. 8, 382383.
Lippmann, M., Albert, R. E., and Laskin, S. (1967). The production of test aerosols for inhalation studies. J. Air Pollut. Control Assoc. 17, 586587.[Medline]
Palekar, L., Kuschner, M., and Laskin, S. (1968). The effect of 3-methylcholanthrene on rat trachea in organ culture. Cancer Res. 28, 20982101.[ISI][Medline]
Pour, P., Stanton, M. F., Kuschner, M., Laskin, S., and Shabad, L. M. (1976). Tumours of the respiratory tract. IARC Sci. Publ. 1, 140
Rusch, G. M., Leong, B. K., and Laskin, S. (1977). Benzene metabolism. J. Toxicol. Environ. Health 2(Suppl.), 2336.
Snyder, C. A., Erlichman, M. N., Goldstein, B. D., and Laskin, S. (1977). An extraction method for determination of benzene in blood by gas chromatography. Am. Ind. Hyg. Assoc. J. 38, 272276.[ISI][Medline]
Snyder, C. A., Erlichman, M. N., Laskin, S., Goldstein, B. D., and Albert, R. (1981). The pharmacokinetics of repetitive benzene exposures at 300 and 100 ppm in AKR mice and sprague-dawley rats. Toxicol. Appl. Pharmacol. 57, 164171.[CrossRef][ISI][Medline]
Snyder, C. A., Goldstein, B. D., and Sellakumar, A. (1978). Hematotoxicity of inhaled benzene to sprague-dawley rats and AKR mice at 300 ppm. J. Toxicol. Environ. Health 4, 605618.[ISI][Medline]
Snyder, C. A., Goldstein, B. D., Sellakumar, A., Bromberg, I., Laskin, S., and Albert, R. (1980). The inhalation toxicology of benzene: Incidence of hemopoietic neoplasms and hematotoxicity in AKR/J and C57BL/6J mice. Toxicol. Appl. Pharmacol. 54, 323331.[CrossRef][ISI][Medline]
Snyder, C. A., Goldstein, B. D., Sellakumar, A., Bromberg, I., Laskin, S., and Albert, R. E. (1982). Toxicity of chronic benzene inhalation: CD-1 mice exposed to 300 ppm. Bull. Environ. Contam. Toxicol. 29, 385391.[ISI][Medline]
Snyder, C. A., Goldstein, B. D., Sellakumar, A. R., and Albert, R. E. (1984). Evidence for hematotoxicity and tumorigenesis in rats exposed to 100 ppm benzene. Am. J. Ind. Med. 5, 429434.[ISI][Medline]
Snyder, C. A., Laskin, S., and Goldstein, B. D. (1975). An extractive method for determination of benzene in blood by gas chromatography. Am. Ind. Hyg. Assoc. J. 36, 833836.[ISI][Medline]
Spiegl, C. J., Leach, L. J., Lauterbach, K. E., Wilson, R., and Laskin, S. (1953). Small chamber for studying test atmospheres. Arch. Ind. Hyg. Occ. Med. 8, 286288.
Stokinger, H. E., and Laskin, S. (1950). Air pollution and the particle-size toxicity problem-II. Nucleonics 3, 1531.
Van Duuren, B. L. (1977). Chemical structure, reactivity, and carcinogenicity of halohydrocarbons. Environ. Health Perspect. 21, 1723.[ISI][Medline]
Wilson, H. B., Sylvester, G. E., Laskin, S., LaBelle, C. W., Scott, J. K., and Stokinger, H. E. (1952). Relationship of particle size of uranium dioxide dust to toxicity following inhalation by animals: II. Arch. Ind. Hyg. Occ. Med. 6, 93104
Wilson, H. B., Sylvester, G. E., Laskin, S., LaBelle, C. W., Scott, J. K., and Stokinger, H. E. (1955). Relationship of particle size of U3O8 dust to toxicity following inhalation by animals. Arch. Ind. Health 11, 1118.
Wilson, H. B., Sylvester, G. E., Laskin, S., LaBelle, C. W., and Stokinger, H. E. (1948). The relationship of particle size of uranium dioxide dust to toxicity following inhalation by animals. J. Ind. Hyg. Toxicol. 30, 319331.[ISI]
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