Perhaps all scientists involved in risk assessment need to become more sensitive to the impact they are having.
In recent years, there has been a great deal of discussion about increasing the participation of stakeholders in decisions that affect human health and the environment. This viewpoint is reflected in the National Research Council report 'Understanding Risk: Informing Decisions in a Democratic Society" and the reports of the Presidential/Congressional Committee on Risk Assessment and Risk Management. Scientists are often included as stakeholders in these documents.
The implication is that scientists, as scientists, have some legitimate role in deciding whether a hazardous waste site should be remediated or a factory sited in a particular location. Some questions that this implication raises are how scientists are defined in these contexts and whether scientists, however defined, should indeed be considered stakeholders in such decisions.
These two questions are closely linked, particularly as related to environmental health. While experts in the field may have differences of opinion as to exactly what risk assessment is, it appears that most consumers of risk assessment information, especially the public, perceive risk assessment as a scientific enterprise and risk assessment values as scientifically generated.
Whatever one's view about risk assessment, it is not science in the sense of an attempt to understand the natural world. Rather, the goal of risk assessment is to provide proscriptive information--at least with respect to human health--as reflected in the fact that risk assessments are based on acceptable daily intake (ADI) values and acceptable cancer risk numbers. Unfortunately for public understanding, the use of substitute terms, such as reference doses rather than ADI, tends to obscure the proscriptive nature of risk assessments.
In addition, while the outcome of risk assessment might logically seem to be a determination of what the risk is, a reading of risk assessment guidelines reveals that, instead, the aim is to determine "safe" values. In the case of noncancer risks, no attempt is made to estimate the risk at these "safe" or "acceptable" levels; instead, they are usually calculated using standardized uncertainty factors, and the end products are considered levels above which risk is indeterminate but acceptable. For cancer risks, the calculated values are based on default "conservative" methodologies. Although these values are described in risk terms, they do not represent the values judged to be scientifically most justified; rather they represent "protective" numbers.
The public perception that risk assessment is a scientific enterprise results not only from a lack of real understanding of the process but also from the fact that scientists often have a major role in generating the final values. Thus, the way that risk assessment is portrayed and the role of scientists in the process lead the public to confuse risk assessment with science and to confuse the risk assessment activities of scientists with other activities that are normally considered scientific. As a result, it is not surprising that members of the public erroneously view the main disseminators of risk assessment information (government officials and some public interest groups) as scientists and thus associate scientists with a specific viewpoint and a stake in the issues in which they are involved.
In a democracy, the ideal is for citizens to become informed about issues and to contribute to decisions by expressing their informed opinions. If they believe that risk assessment numbers are scientific results and that those who produce them are acting scientifically, then they are misinformed; this is one source of what can only be called the plethora of "political" (politicized) science that is found in media presentations on environmental health. Parenthetically, this misinformation also makes science more vulnerable to the arguments of those who claim that all science is totally socially constructed--a claim that is destructive to all science, not only that related to environmental health.
If this analysis is anywhere near the mark, restructuring the way risk management is done by inclusion of stakeholders and changes in decision processes will not be sufficient to ensure either the most democratic or the most efficient process of protecting public environmental health. In addition to restructuring, there must be greater utilization of independent advice that is truly scientific in nature, and there must be a concerted effort to undo past confusion about the relationship of science to risk assessment and the role of scientists in the process.
There have been examples of better use of scientific input in risk decisions: e.g., the use of a scientific advisory committee to provide independent advice to a community in Colorado that was in conflict with the EPA about the necessity for a cleanup of lead in soil. However, inclusion of independent advice is very much the exception; a more formal mechanism needs to be established to ensure that independent advice is reviewed on a regular basis.
There seems to be less progress in undoing current confusion, although there is a lot of discussion about putting "more science" into risk assessment. Perhaps all scientists involved in risk assessment need to become more sensitive to the impact they are having, to work together to find ways to better communicate both the scientific and nonscientific aspects of what they are doing, and to clearly differentiate scientific results from the uses to which these results will be put.
In an ideal world, it might be possible to envision a society of scientifically literate, and even toxicologically literate, citizens who can understand the nuances of environmental health issues. While this is a worthwhile goal, it is not likely to be achieved, at least anytime soon. Meanwhile, scientists who are involved in environmental risk issues can help to achieve the aim of an informed citizenry by more clearly communicating scientific knowledge and indicating the role that policy considerations play in their conclusions.
Michael A. Kamrin
Institute for Environmental Toxicology
Michigan State University
East Lansing, Michigan
In the event of availability of suitable inducers, it might be
possible to tune up our physiological system to obtain
greater protection against toxic, carcinogenic,
immunosuppressive, and infectious agents.
Some 3,000 million years ago, when the first living cell evolved on the surface of the earth, it had to struggle hard to survive in the face of seemingly insurmountable environmental odds. It traversed a long and arduous path to become a more organized form able to cope with adverse circumstances. Manipulations of genomic organization were required to adapt to the changing circumstances. The result was the evolution of more organized life forms--from photosynthetic bacteria to man. In the evolutionary pathway, more than 99% of all species of living organisms that existed at one time or the other are now extinct, and they have no present day descendants. The surviving species were better equipped to transform into nonlethal mutants as a result of chemically and physically induced changes in the genomic sequences. Thus, it was possible to select the best suited to survive the contemporary environmental conditions of life. The result was the evolution of stress response genes, which appear to be one of the most highly conserved and abundant genomic sequences found in nature.
A large volume of published literature suggests that there are unique genomic sequences which impart high efficiency for survival of the organism. They are conserved in the genome even across species barriers. These genes appear to be activated to cope with certain stressful events, such as heat shock, metabolic stress exposure to microgravity, hydration, genotoxic stress, oxidative stress, osmotic stress, radiation stress, and chemical and carcinogenic stress.
We know that there is an intrinsic urge in any organism to adjust itself to the prevalent conditions, adjust itself to come back to a normal or steady state conducive for perpetuation of life. All organisms are continuously being exposed to environmental, toxic, physiological, and metabolic stressors. But they are not always harmed because they possess the intrinsic capabilities to withstand divergent types of stresses. Those inherent mechanisms of stress resistance are, therefore, our evolutionary gains.
It is only logical to assume that a large number of genes may have organized themselves together in the form of a superfamily. Such genes act and function in harmony as per the needs of the organism. Although the nature of the stressors used may be different, the reactions they induce may be similar in nature (1). Sometimes a particular type of stressor may induce a large array of reactions that protect the host from altogether different types of physical, chemical, and biological stressors and from a wide variety of toxic or carcinogenic chemicals (2-9). These observations provide us with the understanding that by using a specific inducer one may be able to activate a large number of gene sequences involved in providing resistance against a host of stressors. As a result of such activation, a large number of biomolecules are produced to abrogate the harmful effects of different stress inducing substances. This appears to be true in case of both biological and chemical stressors (4,5).
While attempting to withstand the onslaughts of the stressful conditions, the organisms may activate specific genes to produce specific proteins, each responsible for counteracting specific or nonspecific stress-induced abnormalities (3-9). Such proteins may have a variety of functions: as enzymes to catalyze biotransformation and detoxification reactions, hormones to potentiate cell proliferation, structural proteins to repair tissue damage, antibodies, cytokines, and growth factors, carrier proteins and enzymes, signal proteins, transcription factors, differentiation factors, etc. Studies carried out on heat shock proteins (hsps) (1) and various other stress-induced proteins (1-10) have yielded a wealth of information. Genes dealing with the resistance mechanisms in microorganisms against the immune attack of the host, in addition to those which induce immunity against them in the host (3,4,6,8) also provided important information regarding the existence of stress response genes. The evolutionary dogma of survival of the fittest therefore lies in the ability of the organisms to perpetuate the stress response genes vis-à-vis the stress resistance genes.
Several immunomodulators that can be considered as stress inducers, such as Bacille bilié de Calmette-Guérin vaccine, Staphyloccus aureus, Streptococcus faecalis, Corynebacterium parvum, Coley's toxin, various viruses, bacterial lipopolysaccharides, lipid A, and protein A, not only potentiate nonspecific immune responses against a variety of bacteria and viruses but also cause regression of various tumors (11). The tumor is a major stress inducer. One of the major outcomes of progressive growth of a tumor is depression of the immune system, which gives rise to total anergy (11). It has been well established that sensitizing the host with small amount of various types of stressors helps activate the host resistance mechanism to fight tumor growth (11).
Induction of stress by calorie restriction provides the host with an increased ability to fight toxic or carcinogenic chemical stress (9). Lipopolysaccharide-induced induction of minor oxidative stress stimulates antioxidant mechanisms such that reperfusion-induced cardiac damage could be lessened (5). It is now well established that the resistance of the myocardium to ischemia can be enhanced both by preconditioning the host and by up regulating the cytoprotective proteins, particularly hsps. An association between heat stress proteins and myocardial protection has been indicated (10). When body temperature in rats increased, both cardiac hsps and catalase activity were increased such that hearts became resistant to ischemia/reperfusion injury. Of greater pathological relevance was the observation that ischaemia itself could induce evolution of hsps and involution of cardiac stress (12) by simultaneously increasing a stress protein and a myocardial antioxidant enzyme, superoxide dismutase (10).
Protein A of S. aureus has been shown to induce antitoxic (3-5), anticarcinogenic (13,14), and antitumor (15) responses, rendering protection to the host against a wide variety of chemical and biological stressors, such as cyclophosphamide, carbon tetrachloride, benzene, dimethyl benzanthracene, Salmonella endotoxin and aflatoxin. Significant protection against the toxic, carcinogenic, and immunosuppressive effects of these compounds was observed with prior sensitization of the host with protein A (5,7,8,16). Further, protein A has been found to cause increased phagocytic response, activate respiratory burst, increase production of interleukins 1 and 2, *-interferon, TNF-*, and also effect an increase in natural killer cell activity, antibody-dependent cell-mediated cytotoxicity, and lymphokine-activated killer cell activity. These properties of protein A, including its ability to elevate the cytotochrome P450-dependent hepatic microsomal mixed-function monoxygeneses and glutathione S-transferases, simultaneously activating the bioelimination process, have been implicated to be responsible for its antitoxic, anticarcinogenic, immunostimulatory, cytoprotective, and cross-tolerance-inducing properties.
The above observations provide some supporting evidence that minute amounts of stress induction may offer increased resistance to either the same or other stressors. One may be tempted to speculate that activation of stress gene superfamilies should be able to provide cross-tolerance of stressors (17). Recently, heat shock protein-peptide complexes have been used as a vaccine against cancer and intracellular pathogens (18).
The phenomenon of induced enzyme synthesis has long been documented. Induced drug resistance in microbes, parasites, and tumor cells has been well established. Striking resemblances exist among such inductive processes. The evolution of hsps in plants, bacteria, and mammalian cells is yet another unique phenomenon. The feedback mechanism to inhibit the production of unwanted excesses of a product is a well-known control mechanism. Elaborate systems to detoxify harmful chemicals exist in various species and are mostly inducible systems. Further, when naturally occurring innate immune resistance fails, induced immune resistance mechanisms prevail. All these phenomena appear to be genomically linked, but they remain dormant or less functional under normal conditions.
The hypothesis which stems out the above is that any stress inducer (physical, chemical, and biological) may effect activation of stress genes including the immune response. Such otherwise dormant genes are made functional to keep our physiological system vigilant to fight the odds. In the event of availability of suitable inducers, it might be possible to tune up our physiological system to obtain greater protection against toxic, carcinogenic, immunosuppressive, and infectious agents.
Prasanta K. Ray
Director
Bose Institute
Calcutta, India
References
1. Hahn GM, Shiu EC, Auger EA. Mammalian stress proteins HSP 70 and HSP 28 coinduced by nicotine and either ethanol or heat. Mol Cell Biol 11(12):6034-6040 (1991).
2. Hayes JD, Pulford DJ. The glutathione S-transferase superfamily: regulation of GST and contribution of the isoenzymes to cancer chemoprotection and drugg resistance. Crit Rev Biochem Mol Biol 30(6):445-600 (1995).
3. Dwivedi PD, Verma AS, Nishra A, Singh KP, Prasad AK, Saxena AK, Dutta KK, Mathur N, Ray PK. Protein A protects mice from depletion of biotransformation enzymes and mortality induced by Salmonella typhimcurium endotoxin. Toxicol Lett 49:1-13 (1989).
4. Raisuddin S, Singh KP, Zaidi SA, Ray Pk. Immunostimulating effect of protein A in immunosuppressed aflatoxin-intoxicated rats. Int J Immunopharmacol 16:977-984 (1994).
5. Maulik N, Watanabe M, Engelman D, Engelman RM, Kagan VE, Kisin E, Tyurin V, Cordis GA, Das DK. Myocardial adaptation to ischemia by oxidative stress induced by endotoxin. Am J Physiol 269:C907-916 (1995).
6. Kagaya K, Miyakawa Y, Watanabe K, Kukazawa Y. Antigenic role of stress-induced catalase of Salmonella typhimurium in cell-mediated immunity. Infect Immune 60(5):1820-1825 (1992).
7. Ray PK, Dohadwala M, Bandopadhyay S. Rescue of rats from large dose cyclophosphamide toxicity using protein A. Cancer Chemo Pharmacol 4:59-62 (1985).
8. Mishra A, Dwivedi PD, Verma AS, Ray PK. Mechanism of enhanced phagocytic response in protein A treated rat macrophages. Immunol Lett 34:289-295 (1992).
9. Turturro A, Hart R. Modulationof toxicity by diet: implications of response at low level exposure. In: Biological Effects of Low Level Exposures: Dose-Response Relationships (Calabrese E, ed). Chelsea, MI:Lewis Publishers, 1994;143-152.
10. Hoshida S, Kuzuya T, Fuiji H, Yamashita N, Oe H, Hori M. Sublethal ischaemia alters myocardial antioxidant activity in canine heart. Am J Physiol 264:1133-1139 (1993).
11. Ray PK, Raychaudhuri S. Immunotherapy of cancer--present status and future trends. In: Immunobiology of Transplantation, Cancer and Pregnancy (Ray, PK, ed). New York:Pergamon Press, 1983;210-239.
12. Currie RW, Karmazyn M, Kloe M, Mailer K. Heat shock response is associated with enhanced postischaemic ventricular recovery. Crit Res 63:543-549 (1988).
13. Kumar S, Shukla Y, Prasad AK, Verma AS, Dwivedi PD, Mehrotra NK, Ray PK. Protection against 7,12-dimethylbenzanthracene-induced tumor initiation by protein A in mouse skin. Cancer Lett 61:105-110 (1992).
14. Shukla Y, Verma AS, Mehrotra NK, Ray PK. Antitumor activity of protein A in a mouse skin model of two stage carcinogenesis. Cancer Lett 103:41-47 (1996).
15. Ray PK, Bandopadhyay S, Mobini J. Inhibition of mammary adenocarcinomas in rats following plasma adsorption over protein A--a potential antitumor agent. Immunol Commun 12(5):453-457 (1993).
16. Paul BN, Saxena AK, Ray PK. In vivo induction of tumor necrosis factor alpha by soluble protein A from Staphylococcus aureus. Immunol Infect Dis 3:295-298 (1993).
17. Ray PK, Srivastava M. A new concept in cancer chemoprevention. Cancer J 26:291-298 (1996).
18. Srivastava PK. Purification of heat shock protein-peptide complexes for use in vaccination against cancer and intracellular pathogens. Methods 12(2):165-171 (1997).
Last Updated: April 23, 1998