Northern Exposures, Northern Risks: Toxicology in Canada

OCTOBER 2008 VOLUME 21, NUMBER 10  Copyright 2008 by the American Chemical Society

Guest Editorial Northern Exposures, Northern Risks: Toxicology in Canada The series Toxicology: A Global PerspectiVe is providing an excellent opportunity to survey the state of the science around the world. Toxicology in Canada faces many of the same challenges and opportunities that have been described in the preceding editorials from Italy, Australia, and other countries. We also have some peculiarly Canadian conditions that arise from our history, geography, and culture; in this Guest Editorial, we will try to convey some of these circumstances. The Eleventh International Congress of Toxicology (ICTXI) was held last summer in Montre´al, Que´bec. This event marked the return of ICT to Canada after an interval of 30 years: The first ICT meeting took place in Toronto, Ontario, at the end of March 1977, following the annual meeting of the Society of Toxicology in the same city. ICTI attendance was nearly 1000, and 30 nations were represented. That first Congress was a milestone in progress toward the establishment of the International Union of Toxicology (1980). Last year, ICTXI attracted more than 1500 participants to Montre´al, representing 70 countries. The Congress was scientifically excellent, efficiently organized, and financially successful, and we are confident that the international reputation of the Canadian toxicology community was strengthened by the success of the meeting.

The Canadian Environment International perception of Canada is dominated by images of the splendor of its natural environment. Visitors expect to find a vast, peaceful land of forests, lakes, and unspoiled wilderness. Canadians themselves may occasionally mock this preconception, because they know that most of us live in urban and suburban centers or in farming country, not far from the southern border with the United States. Nevertheless, the Canadian wilderness image is no myth. Calgary, Alberta, is a booming city, with a population of over 1 million, but it is still possible (as happened this summer) for a wild moose to wander onto the University of Calgary campus. Even in southern Ontario, gridded by superhighways, black bear sightings are sufficiently common that the province runs an educational

program to remind people of appropriate precautions for keeping the animals away. Very few Canadians live in the vast northern and Arctic expanses of the country. The territory of Nunavut stretches north from Manitoba toward the North Pole and covers an area more than four times the size of California, but the number of inhabitants is less than half of the undergraduate student enrollment at the University of Toronto! Nevertheless, the Idea of North (as expressed in a 1967 radio documentary by the celebrated Canadian pianist Glenn Gould) dominates the Canadian imagination much as the outback does in Australia or the western frontier has in the United States. In this context, it is not surprising that a commitment to preservation of the environment is a strong Canadian value. Environmental activist and (academic geneticist) David Suzuki is widely regarded as a Canadian hero. Greenpeace, perhaps the world’s best known environmental protection organization, began in Canada, energized by opposition to U.S. underground nuclear testing in Alaska. Canadians also recognize that the same economic developments that have made the country wealthy directly threaten the wilderness environment that we treasure. A pulp mill is discharging toxic effluent into that white-water kayaking river (1); nickel, gold, and uranium mines despoil the forests of the Canadian shield (2); asbestos is still mined in Quebec (3); and the exploitation of the Alberta tar sands hydrocarbon depositssone of the largest contributors to greenhouse gas production in human historysis creating enormous artificial lakes (“tailing ponds”) contaminated with toxic naphthenic acids (4, 5). (The Alberta government has recently responded to growing public concern about the environmental impact of the tar sands projectsnot by remediation but by launching a $25 million public relations and advertising campaign.) Studies of anthropogenic contamination of the northern environment and its wildlife are a prominent theme in Canadian toxicology. In Arctic conditions, where plants are sparse and growth is slow, pollutants persist longer. Northern First Nations

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peoples relying on a traditional country food diet, rich in animal protein and fat, may face increased exposure to bioaccumulative toxicants. Many Canadian researchers have examined organic pollutant profiles, both in humans and in fauna of the north (6-8). Public awareness of environmental and toxicological issues is high in Canada. Occasionally, political pressure can influence governments to adopt a leadership position with respect to environmental protection. A well-publicized recent example is the decision of the Canadian federal government (April 2008) to implement a ban on polycarbonate baby bottles containing bisphenol A, the first country to do so. When powerful economic interests are threatened, however, action may be delayed almost indefinitely. A striking and shameful example is that Canada not only continues to produce asbestos but, indeed, actively promotes export sales of this toxic material to less-developed nations.

Development of Academic Toxicology in Canada A relatively young nation, established in 1867, Canada cannot boast such venerable traditions as are described by our Italian colleagues (April), who refer to Emperor Nero, Lucretia Borgia, and Bernardo Ramazzini. Industrial development generally came later to Canada than to western Europe and the United States. Occupational diseases, including cancers, have usually been observed in Canada only subsequent to their identification elsewhere [e.g., aromatic amine-induced bladder cancer, lung cancer among coke oven workers, and sinus and laryngeal cancer among workers in nickel refineries (9)]. Toxicology research and teaching have developed at several Canadian universities, and a few examples are given here. This is not a comprehensive list, and we apologize for the inevitable omissions. At the University of Toronto, toxicology has long been a component of the Department of Pharmacology (established in 1887). Velyien Henderson (1877-1945), who became Professor of Pharmacy and Pharmacology in 1907, helped to establish experimental pharmacology and toxicology in North America and is remembered for the discovery (1929) of the anesthetic action of cyclopropane (10). Toxicological research has flourished in that department with the contributions of, among others, Werner Kalow, a pioneer of the field now referred to as pharmacogenetics (11); Alan Okey, toxicology of the aryl hydrocarbon receptor (12); and Denis Grant, aromatic amine toxicology and the genetics of the human arylamine Nacetyltransferases (13). In 2007, the department was renamed the Department of Pharmacology and Toxicology. Gabriel Plaa was recruited to the Universite´ de Montre´al Department of Pharmacology in 1968 and has contributed notably to the promotion of Canadian toxicology, most recently as Honorary President of ICTXI. Plaa’s research work has included studies of chlorinated hydrocarbon hepatotoxicity and its potentiation by aliphatic ketones (14). Dr. Plaa has also been a tireless advocate for the professional development of toxicologists, through the Society of Toxicology, International Union of Toxicology (IUTOX), and Society of Toxicology of Canada (STC) (15). The Universite´ de Montre´al was also the venue of the Medical Research Council Group in Drug Toxicology (1971-1978), later replaced by a provincially funded Occupational Medicine and Environmental Health Department (De´partement de Sante´ Environnementale et Sante´ au Travail) chaired by Jules Brodeur (16). The University of Saskatchewan established a Toxicology Research Centre under the leadership of Bruno Schiefer in 1982

and developed a successful program in both environmental and clinical toxicology research. Cancer research has been a strong and well-supported field in Canada for many years. Harold Johns (1915-1998; University of Saskatchewan and, later, the Ontario Cancer Institute and University of Toronto), the pioneer of cobalt-60 radiation therapy, left a legacy of strength in the basic science of cancer research. With respect to toxicology, a notable Canadian contribution has been made to the study of chemotherapy drug resistance, where the characterization of drug-transport proteins has led to discoveries with broad significance to the action of xenobiotics on mammalian cells. Victor Ling (University of Toronto and presently University of British Columbia) discovered P-glycoprotein (1976) (17). Susan Cole (Queen’s University, Kingston, Ontario) discovered MRP1 (18), an efflux pump important not only for cellular resistance to anticancer drugs, such as doxorubicin, but also for removal of glutathione and glucuronic acid-conjugated xenobiotics from the cell (19). Dating back to 1854, the Department of Pharmacology and Toxicology at Queen’s has been a leading center for toxicology research in Canada, with, among others, the scientific contributions of Gerald Marks on heme alkylation by xenobiotics (20) and William Racz on the toxicity of agents including acetaminophen, methylmercury, and 1,1-dichloroethylene (21). At the University of Guelph, Ontario, the work of Donald J. Ecobichon in the 1960s (subsequently at Dalhousie University, Halifax, Nova Scotia, and McGill University, Montre´al, Que´bec) and Steven Safe (now Director, Center for Environmental and Genetic Medicine, Texas A&M University) in the 1970s provided impetus for the establishment of a successful interdepartmental undergraduate degree program in toxicology, and toxicology research is a theme in diverse departments across the campus. Guelph has also hosted the headquarters of the Canadian Network of Toxicology Centres. In Que´bec, the Environmental Health Research Network (Re´seau de Recherche en Sante´ Environnementale), supported by the Fonds de Recherches en Sante´ du Que´bec, a human health-focused provincial funding agency, is comprised of more than 50 scientists. The network’s activities are organized around four technological platforms: Biomarkers, Toxicogenomics, Drinking Water Contaminants and Modeling, and Environmental Epidemiology. The network is also a partner in the development of numerous government funding initiatives in human environmental toxicology. The natural sciences counterpart to this network is the Centre Interinstitutionnel de Recherche en E´cotoxicologie du Que´bec, which focuses on ecotoxicology. The University of Quebec is a network of 10 universities, the majority of which are involved in toxicology research; there are graduate training programs in toxicology and environmental health at the Institut National de la Recherche Scientifique (INRS, a graduate university), Universite´ du Que´bec a` Montre´al (UQAM), Universite´ de Montre´al, and McGill University. Toxicology research at INRS is conducted primarily at INRSInstitut Armand-Frappier, in the Montreal suburb of Laval. Faculty associated with the Universite´ de Montre´al Human Toxicology Research Center conduct research in toxicokinetics and modeling (22), biomarker development, mixtures, metals, and industrial hygiene. The Department of Pharmacology and Therapeutics at McGill University is focused on developmental and reproductive toxicology. Toxicology research is also pursued in several government departments and agencies. Health Canada, a federal government ministry, incorporates a Toxicology Research Division, housed in Ottawa, which investigates genotoxic, reproductive, and

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neurotoxic effects of chemicals, especially agricultural chemicals and natural food toxicants. The Institut National de la Sante´ Public du Que´bec focuses on human toxicology and has developed an international reputation for its assessment of the effects of organochlorine contaminants on the health of native people.

The Society of Toxicology of Canada The national organization of Canadian toxicologists is the Society of Toxicology of Canada. The genesis of STC was a consensus, among research scientists in several pharmaceutical companies in the Montreal area, that the Canadian toxicology required more vigorous support. From the outset, the group believed that a broad base of scientists from industry, government, and academia should be able to interact through the organization, and this tripartite philosophy has been maintained throughout. At the 1965 founding meeting, the name Canadian Association for Research on Drug Safety (CARDS) was adopted; this name mutated first to CART (Canadian Association for Research in Toxicology) and, in 1979, to the Society of Toxicology of Canada. Annual scientific symposia have been held since 1967, and membership is now more than 300.

Funding of Toxicology Research in Canada The series of editorials has demonstrated that Canada is by no means unique in lacking a reliable and targeted mechanism for funding toxicological research. For example, in the contribution from Australia (23), it was noted that “...introduction of specialized Toxicology Grant Committees by the major funding agencies...would greatly strengthen the discipline.” Similar difficulties exist here. Canada has no national centers for toxicology comparable to the U.S. Environmental Protection Agency or National Institute of Environmental Health Sciences. Consequently, toxicology research funding has been sporadic and unreliable. In 2000, the major federal health research granting agency, the Medical Reserach Council of Canada, was expanded, reorganized, and renamed as the Canadian Institutes of Health Research (CIHR). Despite the similarity of name to the National Institutes of Health, United States, CIHR is not a bricks-andmortar research center; it consists of “virtual” institutes, which coordinate academic health science research in universities and medical schools across the country. Despite pleas from the pharmacology and toxicology research communities, at the time of its establishment, the 13 CIHR Institutes did not provide any natural “home” for these disciplines. Instead, most of the institutes were designed with a specific disease focus (cancer research, circulatory and respiratory health, musculoskeletal health and arthritis, etc.) or with a health services delivery focus (Aboriginal peoples’ health, gender and health, health services and policy research, mental health and addiction, population and public health, etc.). While the intentions of each of these institutes are laudable, none of them can be expected to regard toxicology as a priority. The Canadian Network of Toxicology Centres (CNTC) is a case study in haphazard science funding. CNTC was formed as an entity in 1988, by an agreement among the Universities of Guelph, the University of Saskatchewan, and CIRTOX (Centre Interuniversitaire de Recherche en ToxicologiesUniversite´ du Montre´al and UQAM). In April 1992, CNTC was funded (5 years, $14.1 million total) as a minor component of the federal “Green Plan”, a national environmental protection strategy. Despite promising beginnings, the hoped-for funding of a

dedicated research facility never materialized, and funding for CNTC dwindled. Robert Gale (24) has summarized the demise of the Green Plan, following the change in government with the 1993 federal election: “The Green Plan was high on symbolic policy initiatives for the Conservative Party. They came up with the strategy and name for the plan. This meant that opposition parties had no vested ownership in the plan...The new Liberal government disagreed with the idea of the plan itself. Rather than reformulate a plan in their own image...they abandoned [it] altogether...and [moved] away from a national and concerted approach to environmental planning.” Withdrawal of funding has left the CNTC “without the resources to extend even the most modest research support to Canadian investigators” (Prof. Leonard Ritter, Executive Director; CNTC Annual Report, 2006-2007). Another transient funding program was the Toxic Substances Research Initiative (TSRI). Initiated in 1998 and managed by Health Canada and Environment Canada, TSRI provided competitive funding to Canadian researchers, totaling $40 million over 4 years. However, the funds were targeted to five specific priorities (persistent organic pollutants, metals, endocrinedisrupting chemicals, urban air, and cumulative effects) delineated as much by the contingencies of political damage control as by scientific considerations, and the TSRI was “sunset” in 2002. Successful nurturing of national scientific capacity requires long-term, sustained, and flexible government support. This is particularly true in Canada, where private sector research and development expenditure lag behind that of many other developed nations. For example, according to OECD (Organisation for Economic Co-operation and Development), statistics on “business R&D intensity” (defined as business enterprise sector research and development expenditure as a percentage of value added in industry), Canada scores only 1.4%, as compared to Sweden, 4.7%; Japan, 3.2%; United States, 2.6%; etc. Pharmaceutical industry discovery-related toxicology research in Canada is generally not strong (Merck-Frosst, AstraZeneca Canada, and Caprion are among the notable exceptions). In recent months, the world prices of metals, petroleum, and agricultural commodities have soared; the impetus of Canadian companies to move from resource-based to knowledge-based strategies, never strong, has been weakened further. Philip Cross, writing in the Statistics Canada publication “Canadian Economic Observer” (October 2007) observes that “The revival of Canada’s resource sector immediately conjures the hoary image of Canadians as ‘hewers of wood and drawers of water’, with all its negative connotations going back to biblical times...This...characterization of our resource sector is outdated...Since 2002 there has been a large shift in the resource sector away from trees and towards commodities found mostly underground, notably oil and metals. Rather than being ‘hewers of wood and drawers of water’, it is more accurate (if less catchy) to say Canadians are ‘conveyers of crude and moilers of metals’.” The long-term implications of these economic trends for Canadian science, especially biological science, are certainly not encouraging. In most instances, Canadian toxicologists have succeeded by “packaging” their research under an alternative “brand name”, such as pharmacology, biochemistry, or cancer research. We concur with the conclusion of our Italian colleagues that “the time has come to resuscitate funding programs that support toxicological research...and to generate a sense of identification that cannot be met by sporadic initiatives...” (25).

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P. David Josephy* Department of Molecular and Cellular Biology College of Biological Science UniVersity of Guelph Guelph, Ontario N1G 2W1 Canada

Daniel G. Cyr INRS-Institut Armand-Frappier UniVersite´ du Que´bec LaVal, Que´bec H7V 1B7, Canada

Acknowledgment. We wish to thank Doug Arnold, Malle´ Jurima-Romet, Tom Massey, Gabbie Plaa, William Racz, and Tim Schrader for helpful discussions.

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