One side is accused of supporting ethnic cleansing; the other of being intellectually naive. Does that sound like the beginning of a fruitful collaboration? Perhaps not, but read on. As we report on page 154, an increasingly bitter spat has emerged between geneticists and economists over a paper that links a country's genetic diversity to its economic development. At its heart, the argument boils down to cold statistics and methodological differences. A team of prominent geneticists and anthropologists at Harvard University in Cambridge, Massachusetts, says that the paper's economist authors did not properly account for historical and cultural connections between genetically similar countries, so correlations are mistaken for cause. The work is part of an emerging trend to blend economics with genetics. Daniel Benjamin, an economist at Cornell University in Ithaca, New York, who is trying to identify the genetic basis for economically relevant traits such as risk aversion, is among those who say that the combination has yet to prove its worth. Nonetheless, he and others assert that understanding how genetics influences individual and international economies has the potential to inform policy. For this to happen, both sides must take seriously the standards, methodology and history of the other. Geneticists have spent years grappling with the difficulties of getting useful information out of genomes. They have made mistakes, and learned from them, and it is naive for social scientists to think that they are immune from these errors, or that they can learn all they need to quickly. Benjamin says that nearly every study that links individual economic traits with specific genetic variants, for example, is riddled with false positives. Social scientists should also remember that human geneticists bear the historical scars of eugenics, and more recent accusations of insensitivity to indigenous populations. Any whiff of biological determinism will draw a strong response. Geneticists, for their part, should acknowledge that quantitative social scientists are experts in measuring human behaviour, both individual and collective. An entire subfield of economics, called econometrics, exists to make sense of data that are just as seemingly random as the string of As, Ts, Cs and Gs that comprises a genome. Moreover, many of the statistical methods that economists now use have their roots in the work of early-twentieth-century geneticists. Closer collaboration between the two fields could unlock the knowledge and expertise of social scientists, enabling them to draw conclusions that geneticists would never have conceived. One hopeful model is the Social Science Genetics Association Consortium, a collaboration between social scientists, geneticists and epidemiologists that aims to bring more rigour to the search for the genetic basis of economic and other behavioural traits. In addition to combining the expertise of scientists in disparate fields, the consortium also has access to dozens of cohorts, encompassing more than 100,000 people. The consortium was started after Benjamin's team uncovered a genetic variant linked to educational attainment in some 2,000 Icelanders, only to find that the association could not be replicated in other populations, raising questions over whether it is real. The group's expertise and infrastructure give it a chance of finding genuine links that will hopefully see geneticists working on follow-up studies, rather than writing angry letters.

Selected immune function parameters were examined in male Fischer 344 rats following (a) induction of enzyme-altered preneoplastic liver foci (EAF), and (b) growth modulation of EAF by 30-day feeding with the food antioxidant butylated hydroxytoluene (BHT). Glutathione S-transferase-P (GSTP)-positive EAF were observed in livers of rats receiving diethylnitrosamine (DEN), 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH) (Solt-Farber procedure), with or without BHT treatment. The induction of EAF and/or 0.5% BHT treatment resulted in a significant reduction in the natural killer (NK) cell activity of splenocytes. PH did not affect NK activity significantly compared with control (no PH) rats. The concanavalin A-induced lymphoproliferative activity of splenocytes was increased in rats with PH compared with those without. A lag in time needed to attain maximum calcium release was observed only in the rats with PH compared with those without PH. None of the treatments affected the phagocytic activity of resident peritoneal macrophages. Only EAF-bearing rats without BHT treatment had increased granulocyte and monocyte levels, while the leucocyte and lymphocyte levels were reduced by the initiator DEN. but not by BHT treatment. Further investigations are necessary to determine whether the observed suppression of NK cell activity during EAF induction and growth modulation by BHT is a contributing factor in enhancement of rodent liver neoplasia by this non-genotoxic food antioxidant.

Mathematically based carcinogen risk assessment is based on a number of prudent default assumptions which are becoming progressively less tenable as new scientific evidence is adduced. For example, the assumptions that all rodent carcinogens will be carcinogenic in humans and that there is no safe dose of any carcinogen may, in specific examples, be shown to be untrue. The mechanisms by which carcinogens exert their effects, especially the induction of DNA lesions, DNA repair of these lesions, and cell proliferation, are considered; it is suggested that with recently developed experimental techniques they might be employed to develop a more biologically based approach to risk assessment and might avoid at least, some of the pitfalls associated with the present mathematically based carcinogen risk assessment models. They might lead to an improved appreciation of the shape of the carcinogen dose–response curve, at least at medium to high exposure levels.

The urinary bladder, ureter, and urethra are part of the urinary excretory system and are exposed to chemicals and their metabolites excreted into the urine. Consequently, they are potential target organs for toxic and carcinogenic compounds. Spontaneous proliferative and neoplastic lesions are uncommon and generally associated with inflammation or calculi. A number of treatment-related lesions can occur including necrosis and ulceration, inflammation, metaplasia, and proliferative non-neoplastic and neoplastic urothelial lesions. Rats have been important models in the study of urolithiasis and urothelial carcinogenesis.

Butylated hydroxytoluene (BHT) is a synthetic, food-use, phenolic antioxidant. It has previously been demonstrated to be operationally non-genotoxic and, in addition, failed to induce biologically significant increases in cellular proliferation in the liver, urinary bladder and thyroid gland on feeding to young adult Wistar rats. Nevertheless, it has been reported to enhance the yield of liver tumors when fed to rats or mice that developed an appreciable background incidence of these tumors without treatment. In order to resolve this situation, cell proliferation in response to BHT treatment was studied in enzyme-altered foci (EAF) induced in male Fischer 344 rats using the Solt-Farber procedure. It was demonstrated that feeding 0.5% dietary BHT for 30 days after the induction of EAF led to a 20- to 30-fold increase in the gamma-glutamyltranspeptidase-positive areas in both DEN- and saline-initiated rat livers, but to no major effects in glutathione S-transferase placental form (GSTP)-positive foci. Cell proliferation rates within EAF and surrounding normal liver were measured using different histological techniques. Nuclear labeling with [3H]thymidine and proliferating cell nuclear antigen (PCNA) over the total hepatocyte population indicated that BHT approximately doubled nuclear labeling in rats initiated with DEN. PCNA labeling in GSTP-positive foci was not affected by BHT. In GSTP-positive foci, evaluation of nucleolar organizer regions (AgNOR), which reflect cell proliferative in addition to transcriptional activity of ribosomal RNA, was achieved using a novel double staining technique. BHT diet did not affect the number of AgNOR per nucleus or the percentage AgNOR area/nucleus. Nevertheless, both PCNA labeling and the AgNOR area per nucleus were significantly greater in GSTP-positive foci compared with non-focal regions in rats fed either BHT or control diets. These results are discussed in the light of further experimental work required to determine the relevance of these data to possible human risk assessment for BHT.

In previous work we have shown that changing the fatty acid composition of a constant amount of fat in a modified AIN-76A diet affected the level of ductular cell proliferation in the mammary glands of young virgin female Swiss Webster mice. In particular, linoleic acid concentrations of 5-10% of the total fat in the diet led to variable but appreciably higher levels of proliferation than did higher levels of linoleic acid. In this report it is shown that feeding low levels of the total fat as alpha-linolenic acid (0-5%) resulted in a similar effect. In addition the effects of other fats including menhaden oil, were further investigated.

A wide variety of oxidative DNA lesions are commonly present in untreated human and animal DNA. One of these lesions, 8-hydroxydeoxyguanosine, has been shown to lead to base mispairing (mutation) on DNA replication. Other lesions remain to be investigated in this respect. Oxidative DNA lesions on cell replication may, in appropriate circumstances, lead to proto-oncogene activation. Oxidative DNA damage, on fixation, may also lead to cytotoxicity followed by regenerative proliferation. The probable or possible importance of oxidative DNA damage is reviewed for various classes of carcinogens and natural processes, including metal ions, high-energy radiation, miscellaneous chemicals, tumor-promoting agents, polyhydroxyphenols/quinones, lipid metabolism, peroxisome proliferators and thyroid function. It is concluded that although the evidence needs considerable strengthening in many of these examples, the available information indicates the potential importance of oxidative DNA damage in the induction of tumors by these agents. It is also possible that non-cancerous degenerative diseases associated with aging are the result of the accumulation of lesions resulting from unrepaired oxidative DNA damage.

Umbelliferous crop plants, including the parsnip (Pastinaca sativa L.), elaborate enhanced levels of furocoumarins, including psoralens, when subjected to biotic or abiotic stress. These furocoumarins are recognized to lead to phototoxicity. In this study, the effect of these agents, which are present in diseased parsnip root tissue, on the liver and two tissues on the route of entry to the body (the oesophagus and forestomach) were investigated. Young male Swiss Webster mice were fed for approximately 30 days with modified AIN-76A diets containing 32.5% dried healthy, 32.5% apparently healthy or 32.5% fungicide-treated parsnip root tissue, and 8, 16 or 32.5% dried diseased (Phoma complanata-infected) parsnip root tissue. As controls, three modified AIN-76A diets differing in their edible starch-to-sucrose ratios (C1-C3) were administered for an equal time. Dried healthy parsnip root tissue, compared with controls, did not significantly affect any of the indices of cellular proliferation or histopathological parameters that were assessed. Histopathological examination of the oesophagus and forestomach demonstrated no significant changes as a result of feeding any of the diets containing parsnip tissue. In the liver, the highest level (but neither of the two lower levels) of dried diseased parsnip root tissue led to swelling of the cytoplasm in cells surrounding the central vein of hepatic lobules, with consequent compression of the peripheral cells. Using [3H]thymidine radioautography, a dose-related increase in cell labelling with the level of diseased parsnip root tissue was demonstrated in the liver. Compared with control diet C2 only, the extent of [3H]thymidine labelling in the liver was increased in mice receiving apparently healthy parsnip tissue; a slight, not statistically significant, increase was also noted with fungicide-treated parsnip tissue. Increased [3H]thymidine labelling with the feeding of diseased parsnip tissue was also found in the greater curvature of the forestomach and the region of the oesophageal-forestomach junction, but not at the glandular junction of the forestomach nor in the mid-oesophagus.

Those chemicals that are added to food during modern processing are most stringently examined for toxic effects and, if they demonstrate toxicity, are strictly controlled. Despite this, a considerable proportion of the North American human cancer burden has been associated with diet and nutrition. The possible contributions of excess calories, excess and wrongly balanced fats, natural contaminants, and naturally occurring carcinogens within the food supply to this horrendous burden of cancer is considered. The theoretically possible use of bioengineering techniques to modify the composition of food crops and thus to minimize the levels of carcinogens in the food supply is discussed. This is considered important since failure to monitor the effect of bioengineering may lead to an increase in the level of such noxious agents, especially if the goal of such bioengineering is to develop food crops with increased intrinsic resistance to pests and other spoilage organisms.

Phenolic antioxidants have been used for many years to prevent oxidative spoilage of food (rancidity). They are of major importance in protecting foodstuffs during transportation and storage. Antioxidants thus constitute an essential element in the modem centralized food processing and distribution industries. In Canada, only three phenolic antioxidants are permitted to be added to food: butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate (PG). The mean dietary intake of BHA and BHT, as a result of their useas food additives, is relatively low; in Canada the intake overall ages is 7.40 mg/person/day for bothBHA and BHT, leading to a combined totalof 0.26 mg/kg/day (Kirkpatrick andLauer, 1986).

Increased cellular proliferation has been associated with the enhanced expression of several key stages in carcinogenesis. A standard protocol was used to investigate the effect of specific dietary regimens on cellular proliferation. Young adult Swiss Webster mice were fed for 30 days with modified AIN-76A semi-purified diets designed to illustrate the effects of the levels of dietary or calorie restriction, different fibers and bulking agents, and different fats on cellular proliferation. Female mice were used for the restriction and fat studies, males for the fiber and bulking agent studies. Vaginal smears were taken from females from treatment day 15, and the mice killed 2 days following the first estrus following 30 days feeding; males were killed on the 30th day. One hour before death, mice were injected ip with 0.25 micro Ci/g 3[H]-thymidine. Slides were prepared for radioautography and histopathology. Both dietary and calorie restriction led to reduced 3[H]-thymidine labeling indices in each of the seven tissues studied, the mammary gland being the most severely affected. Different fibers and bulking agents, in specific cases, reduced labeling in the duodenum but not to a consistent statistically significant extent in the colon or colo-rectal region. In the duodenum, oat bran and oat gum were the most effective while wood cellulose (alphacel) had no effect. Investigations on the effects of different fats is continuing. High levels of lard, menhaden oil, or cod liver oil as the fat component of the AIN-76A diet, led to much higher levels of labeled cells in the mammary gland or colo-rectal region than did fat components rich in vegetable oils. The labeling indices appeared to be inversely correlated with the level of linoleic acid in the diet, a presumption that has been confirmed by investigating a series of diets containing different levels of this acid. Anti-oxidants were not used in any of these fat-modified diets. The overall results obtained in these studies clearly indicate the utility of cellular proliferation studies in investigating the effects of dietary modifications.

Young virgin female Swiss Webster mice were fed AIN-76A semi-purified diets containing equal weights of different fats for approximately 30 days. Using [3H]thymidine radioautography, it was established that mice fed 100% lard or high levels of fish oils (menhaden oil or cod liver oil) developed elevated cellular proliferation in the duct cells of the mammary gland and an increased number of labeled cells/crypt in the crypts of the colo-rectum accompanied by an increase in the size of the proliferative compartment. A possible inverse correlation between the level of [3H]thymidine labeling in the mammary gland, but not in the colo-rectum, and the linoleic acid content of individual diets may help to explain the significance of these observations. The effect of adding an antioxidant mixture to these diets was to reduce the excess proliferation induced in the intestinal crypts by lard or fish oil to the level induced by soybean oil, but only partially so in the duct cells of the mammary gland.

Rodent carcinogens may, for physiological or other reasons, induce cancer by a variety of mechanisms which vary in their ability to affect humans. While the current approach of some regulatory agencies to carcinogen risk assessment and regulation may possibly be justified with most genotoxic carcinogens, this is not true with all nongenotoxic carcinogens. Mechanisms attributable to high dose toxicity occasioned by misuse of the maximum tolerated dose concept, imbalancing of homeostasis, unphysiological conditions, and induced cellular proliferation are reviewed. The greatest present need for meaningful regulation of carcinogens is to obtain public acceptance of the fact that some carcinogens are species specific and probably will not exert their effects in humans.

There is much experimental but very limited clinical evidence that dietary restriction has a beneficial effect in reducing the incidence of naturally occurring and induced cancer formation. Restriction has also been suggested to be advantageous in other respects (Weindruch et al. 1986), including increasing longevity and improving the effectiveness of certain aspects of the immune system. The effect of dietary and caloric restriction on experimental carcinogenesis has been recognized for many years, the sentinel observations being due to Tannenbaum (1940a, 1942; Tannenbaum and Silverstone 1957). Many others have confirmed Tannenbaum’s initial observations (Andreou and Morgan 1981; White 1961; Ross and Bras 1973; Klurfeld et al. 1987). Information on the possible advantageous effect of dietary restriction in humans has proved much more elusive. Although Tannenbaum (1940b) obtained some evidence for a correlation between excessive body weight and cancer from human insurance records, further information has not been adequate to demonstrate this conclusively. In fact, there is a major controversy whether mammary and colonic tumorigenesis in humans is dependent on the high lipid content of the North American diet or on excess calories [National Academy of Sciences (USA) 1980, 1982].

The relevance of rodent cancer bioassay data to humans is discussed in relation to the needs of regulatory agencies. The usefulness of in vivo and in vitro genotoxicity testing in this connection is also discussed. In the case of rodent carcinogens that do not elicit genotoxicity, it is suggested that homeostatic imbalance, cell proliferation, and other processes may play a major role in tumor development and its importance to the possible ability of the test agent to induce human cancer. These possibilities need to be evaluated on a case by case basis. The methods by which chemicals are selected for the rodent cancer bioassay are also discussed and it is pointed out that naturally-occurring constituents of human foods should in future receive greater priority as a consequence of anticipated changes resulting from biotechnology.

Cancers arise in specific tissues. One difficulty with the present definitions of the Maximum Tolerated Dose (MTD), as they pertain to the rodent cancer bioassay, is that they base MTD on relatively crude parameters associated with the well-being of the entire animal rather than with the lack of specific tissue toxicity. Additional factors that could be included in the MTD definition, or could be separately determined, are addressed. Many of these factors refer to toxic behavior in one or a few tissues and, if used in setting the MTD, may mask more relevant events occurring at higher dose levels in other tissues. Reducing the MTD to a level that fails to take into account pesticide or drug-related toxicity may lead to the loss of relevant information in the bioassay. It is concluded, therefore, that there are two possible approaches to a more appropriate use of the MTD. The highest dose of the test agent (MTD) may be chosen (i) to lie below the thresholds of carcinogenicity-related non-genotoxic toxicity or (ii) the present high level MTD may continue to be used and tumors that arise may be classified as being irrelvant to humans at some or all exposure levels. The latter approach is to be preferred. It has the potential to avoid missing high level effects of the test agent that may be relevant to the human population.

Forestomach neoplasia induced by the apparently non-genotoxic carcinogens, butylated hydroxyanisole and propionic acid, appears to arise by way of sustained high levels of cellular proliferation. Several other inducers of enhanced cellular proliferation, or the consequential incidence of hyperplastic lesions, have been identified in the rodent forestomach but the requisite carcinogenicity bioassays remain undone. In other tissues, such as the male rat kidney, the rodent thyroid follicular cell and the bladder epithelium, there is also evidence supporting the concept that sustained enhanced cellular proliferation may be an important early marker for non-genotoxic carcinogens. This reaction is, however, not likely to be the only marker necessary for the identification of non-genotoxic carcinogens.

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More

The process of health risk assessment has been the subject of systematic study in recent years. For example, interdisciplinary groups established by the U.S. National Research Council (NRC 1983) and the World Health Organization (WHO 1985) have developed models for risk assessment and risk management. These investigations have provided clear frameworks within which questions pertaining to health risks may be addressed. This has proven useful in distinguishing between the scientific and extrascientific dimensions of risk assessment, and in ensuring that all relevant factors are given proper attention in risk management decisions.