MAY 2008 VOLUME 21, NUMBER 5 Copyright 2008 by the American Chemical Society
Guest Editorial Toxicology Down Under: Past Achievements, Present Realities, and Future Prospects Introduction The smallest of the continental land masses (7.6 × 10 km ), Australia is home to 21 million inhabitants who enjoy a stable political democracy and a standard of living that ranks among the most prosperous nations of the world. Given the harsh, arid environment that prevails beyond the coastal margins of the continent, the growth of human settlements to their present proportions was not a foregone conclusion, particularly in the earliest days of European colonization. Geographical isolation, together with the inhospitable hinterland, has ensured that the Australian ecosystem supports an extraordinary biodiversity and that many species of plants, insects, and animals enhance their survival prospects by producing a staggering array of chemical defenses, potent venoms, and noxious poisons. In the plant kingdom alone, some 1000 or so native species are toxic to humans or livestock (1). A 1985 estimate of the economic impact of stock loss due to plant poisoning in the Australian rural sector ran in excess of $80 million dollars a year (2). This ubiquity of natural toxicants presented strong challenges not only to the European settlers after their arrival in the late 18th century but also to the original indigenous inhabitants. My brief review of the status of toxicology in Australia must therefore begin with the ingenuity displayed by its Aboriginal peoples in surmounting the toxic threats that faced them. 6
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Past Challenges: Early Australians and Toxic Plants Drawing on insights gained during their hunter and gatherer existence over thousands of years, Australian Aborigines adeptly exploited the toxic properties of plants when hunting for prey, including the use of crushed Austral indigo leaves to stun fish within rock pools or the addition of stupefying cycad berry extracts to waterholes frequented by marsupials (1). As with other traditional peoples, indigenous Australians excelled in the use of simple technologies to detoxify noxious plants prior to human consumption (3, 4).
The efficacy of these indigenous practices in rendering toxic plants edible was demonstrated repeatedly following the arrival of European explorers. One of the earliest descriptions of a toxicological phenomenon on the Australian continent appears in the EndeaVour journal of the English botanist and natural historian Sir Joseph Banks (Figure 1). Often called “the Father of Australia” on account of his advocacy of English settlement of “New Holland”, Banks supervised scientific proceedings during Captain James Cook’s 1770 exploration of the eastern Australian coastline in the HMS EndeaVour. In his journal, Banks describes the experiences of pigs and crew members after they consumed berries from a “palm” that grew in Northern Queensland, most likely Cycas media: “[The “palm”]...generally bore a plentiful crop of nutts [sic] about the size of a large chestnut and rounder. By the hulls of those which we found near the Indian fires we were assured that these people eat them, and some of our gentlemen tried to do the same, but were deterrd [sic] from a second experiment by a hearty fit of vomiting and purging which was a consequence of the first. The hogs however were still shorter of provision than we were eat them heartily and we concluded their constitution stronger than ours, till after about a week they were all taken extreemly [sic] ill of indigestions; two died and the rest were savd [sic] with difficulty” (5). The diarrhea and vomiting described by Banks suggests intoxication with β-glycosides such as cycasin and macrozamin, which on processing by bacterial β-glycosidases in the gastrointestinal tract generate the toxic aglycone methylazoxymethanol (Figure 1) (6). The latter is well-known to experimental toxicology on account of its mutagenicity, carcinogenicity, hepatotoxicity, and neurodevelopmental toxicity (7, 8). Methylazoxymethanol undergoes spontaneous fragmentation and CYP2E1-catalyzed metabolism to a range of noxious and electrophilic species including formic acid, formaldehyde, and methylcarbonium ions (9, 10). Captain Cook’s men omitted key steps used by Aborigines during the preparation of cycad berries,
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Figure 1. (A) Sir Joseph Banks, chief botanist of the HMS EndeaVour voyage, which supplied one of the earliest descriptions of a toxicological phenomenon in Australian history. This image was used with the permission of the Trustees of the Royal Botanic Gardens, Kew. (B) Biochemical basis for the toxicity of cycad β-glycosides.
which variously included heating, sun drying, and elution under running water to minimize dietary exposure to β-glycosides (1, 4). The EndeaVour expedition was not the first to be afflicted by plant intoxications of this kind. A century earlier, Dutch explorers of the southwestern coastline of Western Australia suffered similar poisonings, probably involving macrozamincontaining berries (Macrozamia riedlei). Wrongly imagining a close similarity to Dutch beans, a number of men ingested Macrozamia berries during an inland excursion near the Swan River in 1697. One of De Vlamingh’s crew recorded in his journal that “I ate five or six of them...but, after an interval of about three hours, I and five others who had eaten of these fruits began to vomit so violently that we were as dead men; so that it was with the greatest difficulty that I and the crew regained the shore” (11). Following the establishment of stable European settlements in coastal areas, an effort was made to explore the unknown inland regions, motivated by a need for quality pasture for livestock as well as the search for a mythical inland sea (12). Plant poisonings disrupted a number of these overland expeditions, including the 1864-1865 journey of the Jardine brothers in Northern Queensland in which 30 horses and 50 cattle were lost following ingestion of a poisonous plant, most likely Erythrophleum chlorostachys (Cooktown ironwood). Ignorance of Aboriginal food technologies also contributed to the failure of one of the most celebrated attempts to find a northern overland route through central Australia from Melbourne, led in 1860 by explorers Burke and Wills (13). Trapped in near starvation in the arid outback region of Cooper’s Creek, the explorers copied the practice of local Aborigines by consuming a native fern (nardoo), ingesting “four or five pounds a day between us” as Wills recorded in his journal. On this diet, the men progressively lost weight and experienced a paralyzing loss of lower body strength. Closer attention to the food practices of local tribesmen might have saved the doomed explorers, since they involved extensive grinding in water and scrupulous avoidance of contamination with cofactor-containing organic matter, measures that counteracted the very high thiaminase levels in nardoo (14). Burke and Wills thus seem to have lost their lives to chronic vitamin B deficiency (beriberi), while John King, the sole survivor, experienced long-term peripheral neuropathy due to chronic thiamine deficiency (14).
The Growth of Australian Toxicology During the 19th and early 20th centuries, the growing availability of ports and rail transport allowed efficient export of Australian agricultural products to distant global markets. Together with gold rushes and mineral exploration, a growing agricultural sector underpinned the steady expansion of the Australian economy during this period, an era in which the whole nation “rode on the sheep’s back” (12). Once again, these successes were not a foregone conclusion since in addition to coping with poor soils, drought, and unpredictable rainfall, Australia’s pastoralists had to learn to minimize sheep, cattle, and horse losses due to intoxication with poisonous plants. During the mid-20th century, efforts to overcome this problem were assisted by the growth of toxicological research competence in universities, agricultural research centers, and government-funded laboratories. In some ways, this period represents the golden age of Australian toxicology, as widescale efforts were made to systematically study the toxicity of native Australian plants. The experience in Western Australia is typical of efforts in the other six states that comprise the Australian Commonwealth. In work that commenced in 1934 at the Avondale Research Station in Beverly, Western Australia, a three decade-long collaboration between the Curator of the State Herbarium, C. A. Gardner, and the senior veterinary pathologist, H. W. Bennetts, produced an exhaustive compendium of the toxicological effects of native West Australian plants, providing information on the target organ for each species, the clinical signs of stock intoxication, and the doses required for induction of toxicity (15). Similar efforts in other Australian states produced comparable handbooks of toxic plants in their respective regions (16, 17). Such knowledge was invaluable to end users of this information within the agricultural sector, but in the preface to the 1956 encyclopedia that is the fruit of the collaborative endeavor between Gardner and Bennetts, the authors concede that even by the standards of the day, their efforts were scientifically incomplete, lamenting that “there is a regrettable lack of knowledge concerning the nature of the toxic principles responsible for the poisonous properties of native species. In most instances these have not been isolated and their chemical structure is entirely unknown” (15). This comment presages the frustrations of many who have worked within Australian toxicology since its inception: Despite the best professional
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intentions on the part of practitioners, a lack of significant resourcessboth institutional, financial, instrumental, and humanshas often hindered the ability to attain the critical mass of scientific competency required to address key toxicological questions in a manner consistent with the highest international standards. In more recent times, Australian toxicological research has tended to maintain its focus on the characterization of toxic threats that have particular relevance in the local setting. Given the historical dominance of agriculture and mining as key drivers of the Australian economy, traditional areas of strength include such topics as plant-derived toxins; toxicological characterization of venoms produced by marine and terrestrial organisms including snakes, spiders, and jellyfish; the production of immunological reagents for use as antidotes against envenomations; and study of the health effects accompanying exposure to toxic metals released during the processing of mineral ores. The latter includes classic investigative work on the epidemiology of environmental lead exposure and its effects on childhood intelligence conducted in South Australia, home of the world’s largest lead smelter (established in Port Pirie in 1884) (18). Moreover, because skin cancer is common due to high levels of solar radiation combined with the outdoor, beach-focused lifestyle of many Australians, local researchers have devoted considerable effort to understanding cellular responses to DNAdamaging doses of UV radiation (19). Over the years, many individual Australians have made outstanding contributions within the domain of toxicologys including, for example, the controversial Sydney-based medical scientist Dr. William McBride, who was one of the first to associate thalidomide ingestion during pregnancy with the birth of malformed infants (20). Particularly far-reaching experiments were performed during the 1960s and 1970s by the eminent University of Queensland pathologist, John Kerr, who defined the ultrastructural features of apoptotic cell death, laying the foundation for mechanistic insights that would revolutionize our understanding of many chemically induced toxic syndromes (21, 22). Strong contributions have also been made, and continue to be made, by research teams in various Australian universities working in the areas of xenobiotic metabolism and the transcriptional regulation of biotransformation pathways (23–28). Notwithstanding these achievements, there are grounds for concern regarding the compounding difficulties currently experienced by toxicology researchers within Australia. The struggles involved in extending the domains of local research beyond those that are simply of concern to Australia must be addressed if the discipline is to take its rightful place alongside other biomedical and chemistry-related disciplines. Of course, since toxicology necessarily has a strong applied focus, it is expected that local issues will strongly influence its evolution within any national setting, a point that has been recognized by others in the present Global Forum series (29). Indeed, the preeminence of toxicology in the United States and Europe seems at least partly due to the historical strength of the pharmaceutical and chemical industries in these regions, creating a sustained demand for toxicological knowledge and, just as importantly, providing a rich array of career options for graduates with toxicological expertise. The lesser contribution of the chemical and pharmaceutical industries to the Australian economy has meant that such forces have not fueled the development of toxicology to anything like the same extent within the local setting. A related point is that during the regulatory evaluation of human and veterinary pharmaceuticals, agrochemicals, and food
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additives, Commonwealth agencies have often relied upon the importation of toxicological knowledge, expertise, and data from abroad. This long-standing practice has further inhibited the development of strong centers for toxicological testing and risk assessment capability within Australia.
Future Prospects for Australian Toxicology In the face of these sobering realities, perhaps the greatest issue facing Australian toxicology is the challenge of performing high-quality research on matters of broad relevance that allow cutting-edge engagement with the wider international research community. This problem has become particularly pressing over the past decade or two with the accelerating international emphasis upon clarifying the molecular and chemical basis for xenobiotic toxicity. For any number of reasons, many of which seem related to chronic under-resourcing, geographical isolation, and the lack of a disciplinary critical mass within most academic centers, Australian toxicological research has struggled to keep abreast of the profound changes that accompanied arrival of the era of molecular medicine. Anecdotally, over the past decade or so, one senses a decline in the number of presentations by Australian researchers at major international toxicology conferences (e.g., IUTOX, SOT, EUROTOX, ACS Division of Chemical Toxicology meetings, ISSX, etc.), an issue that prompts concern over the discipline’s future viability. A number of avenues of action can be suggested to reverse the fortunes of toxicology within Australia. Given that I am an academic researcher working within the higher education system, my remedies will inevitably be biased from that standpoint: Others may propose alternative yet equally sensible course of actions. First, the introduction of specialized Toxicology Grant Committees by the major funding agencies of the Commonwealth Government [such as the National Health and Medical Research Council (NH&MRC) and the Australian Research Council (ARC)] would greatly strengthen the discipline. The NH&MRC is the main agency that funds Australian health-related research, and over the past decade, it has improved its system of evaluating funding applications by adopting an NIH-style model involving panels comprised of experts with a particular disciplinary or disease focus. For most disciplines, this system ensures that applications are channeled to suitably qualified assessors, but to date, no specialized committee has been created for the evaluation of toxicology applications. The recent announcement that the NIH and NIEHS will introduce a Special Emphasis Panel devoted to reviewing proposals to explore the systemic toxicity of environmental chemicals is good news for the toxicology community within the United States; one hopes that this NIH initiative will encourage Australian funding agencies to explore similar measures. Second, the failure of Australian toxicologists to organize themselves into a broad-based yet unified scientific society may be one reason why their discipline has lagged in recent times. The establishment of an “Australian Toxicology Society” modeled along the lines of those in countries such as the United Kingdom, United States, Japan, China, and continental Europe that incorporates the full breadth of the contemporary toxicological research enterprise would provide a galvanizing impetus to the discipline. Such a body might also actively lobby Commonwealth funding agencies to redress such deficiencies as the lack of specialized toxicology grant review panels highlighted above. Third, and perhaps most importantly, steps should be taken to reverse the erosion of toxicological research strengths within
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Australian universities that has occurred in response to the growing dependence on undergraduate teaching to maintain departmental revenues. Under Commonwealth government funding policies of recent years, there has been a growing drift of “research-only” investigators into comparatively well-funded and well-equipped research institutes, leaving many university teaching departments with an aging and inadequate research infrastructure. These forces have limited the ability of academic toxicologists to explore mechanistically demanding research questions that address the fundamental molecular mechanisms of chemically induced disease. Consequently, there are a dwindling number of Australian centers where young scientists can gain rigorous training in molecular toxicology using state of the art methodologies. This problem might be less severe if some of the research institutes that have emerged around Australia in recent years had cultivated an emphasis upon the molecular aspects of xenobiotic toxicity, but to date, this has not tended to occur. Attention to this and the above-mentioned issues would help Australian toxicology emerge from its present lethargic state to a position of improved international competitiveness. Philip C. Burcham Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, The UniVersity of Western Australia, Nedlands, WA 6009, Australia Tel:61-8-9346 2986 Fax: 61-8-9346 3469 E-mail:
[email protected] References (1) Everist, S. L. (1974) Poisonous Plants of Australia, Angus and Robertson, Sydney, Australia. (2) Culvenor, C. C. J. (1985) Economic loss due to poisonous plants in Australia. In Plant Toxicology (Seawright, A. A, Hegarty, M. P, James, L. F., and Keeler, R. F., Eds.) pp 3-13, Queensland Poisonous Plants Committee, Yeerongpilly, Australia. (3) Oelrichs, P. B., Macleod, J. K., Seawright, A. A., and Ng, J. C. (1997) Isolation and characterisation of urushiol components from the Australian native cashew (Semecarpus australiensis). Nat. Toxins 5, 96–98. (4) Farer, K. (2005) To Feed a Nation: A History of Australian Food Science and Technology, CSIRO Publishing, Collingwood, Australia. (5) Beaglehole, J. C. (1962) The EndeaVour Journal of Joseph Bankss1768 to 1771, Vol. 2, Angus and Robertson, Sydney, Australia. (6) Schneider, D., Wink, M., Sporer, F., and Lounibos, P. (2002) Cycads: their evolution, toxins, herbivores and insect pollinators. Naturwissenschaften 89, 281–294. (7) Sieber, S. M., Correa, P., Dalgard, D. W., McIntire, K. R., and Adamson, R. H. (1980) Carcinogenicity and hepatotoxicity of cycasin and its aglycone methylazoxymethanol acetate in nonhuman primates. J. Natl. Cancer Inst. 65, 177–189. (8) Talamini, L. M., Koch, T., Ter Horst, G. J., and Korf, J. (1998) Methylazoxymethanol acetate-induced abnormalities in the entorhinal cortex of the rat; parallels with morphological findings in schizophrenia. Brain Res. 789, 293–306.
Editorial (9) Fiala, E. S., Sohn, O. S., Puz, C., and Czerniak, R. (1987) Differential effects of 4-iodopyrazole and 3-methylpyrazole on the metabolic activation of methylazoxymethanol to a DNA methylating species by rat liver and rat colon mucosa in vivo. J. Cancer Res. Clin. Oncol. 113, 145–150. (10) Sohn, O. S., Ishizaki, H., Yang, C. S., and Fiala, E. S. (1991) Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P4502E1. Carcinogenesis 12, 127–131. (11) Anonymous (1701) Extract from the journal of a voyage made to the unexplored south land, by order of the Dutch East India Company, in the years 1696 and 1697, http://gutenberg.net.au/ebooks06/0600361h. html, Chapter 12. (12) Blainey, G. (1994) A Shorter History of Australia, William Heinemann, Port Melbourne, Australia. (13) Clune, F. (1981) Dig: The Burke and Wills Saga, Angus and Robertson, Sydney, Australia. (14) Earl, J. W., and McCleary, B. V. (1994) Mystery of the poisoned expedition. Nature 368, 683–684. (15) Gardener, C. A., and Bennetts, H. W. (1956) The Toxic Plants of Western Australia, West Australian Newspapers, Perth, Australia. (16) Hurst, E. (1942) Poison Plants of New South Wales, Poison Plant Committee of N.S.W., Sydney, Australia. (17) Webb, L. J. (1948) Guide to the Medicinal and Poisonous Plants of Queensland, Bulletin 232, Council for Scientific and Industrial Research, Melbourne, Australia. (18) McMichael, A. J., Baghurst, P. A., Wigg, N. R., Vimpani, G. V., Robertson, E. F., and Roberts, R. J. (1988) Port Pirie Cohort Study: Environmental exposure to lead and children’s abilities at the age of four years. N. Engl. J. Med. 319, 468–475. (19) Reeve, V. E., and Tyrrell, R. M. (1999) Heme oxygenase induction mediates the photoimmunoprotective activity of UVA radiation in the mouse. Proc. Natl. Acad. Sci. U.S.A. 96, 9317–9321. (20) McBride, W. G. (1961) Thalidomide and congenital anomalies. Lancet 2, 1358. (21) Kerr, J. F. (1965) A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J. Pathol. Bacteriol. 90, 419–435. (22) Kerr, J. F., Wyllie, A. H., and Currie, A. R. (1972) Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257. (23) Rowland, A., Gaganis, P., Elliot, D. J., Mackenzie, P. I., Knights, K. M., and Miners, J. O. (2007) Binding of inhibitory fatty acids is responsible for the enhancement of UDP-glucuronosyltransferase 2B7 activity by albumin: implications for in vitro-in vivo extrapolation. J. Pharmacol. Exp. Ther. 321, 137–147. (24) Johnston, W. A., Huang, W., De Voss, J. J., Hayes, M. A., and Gillam, E. M. (2007) A shuffled CYP1A library shows both structural integrity and functional diversity. Drug Metab. Dispos. 35, 2177–2185. (25) Butcher, N. J., Tetlow, N. L., Cheung, C., Broadhurst, G. M., and Minchin, R. F. (2007) Induction of human arylamine N-acetyltransferase type I by androgens in human prostate cancer cells. Cancer Res. 67, 85–92. (26) Fiala-Beer, E., Lee, A. C., and Murray, M. (2007) Regulation of the rat CYP4A2 gene promoter by c-Jun and octamer binding protein-1. Int. J. Biochem. Cell Biol. 39, 1235–1247. (27) Chapman-Smith, A., and Whitelaw, M. L. (2006) Novel DNA binding by a basic helix-loop-helix protein. The role of the dioxin receptor PAS domain. J. Biol. Chem. 281, 12535–12545. (28) Hempel, N., Negishi, M., and McManus, M. E. (2005) Human SULT1A genes: cloning and activity assays of the SULT1A promoters. Methods Enzymol. 400, 147–165. (29) Loureiro, A. P., and Augusto, O. (2008) Toxicological issues in Brazil range from long-standing problems to novel challenges. Chem. Res. Toxicol. 21, 267–271.
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