Hormesis: changing view of the dose-response, a personal account of the history and current status.

This paper provides a personal account of the history of the hormesis concept, and of the role of the dose response in toxicology and pharmacology. A careful evaluation of the toxicology and pharmacology literatures suggests that the biphasic dose response that characterizes hormesis may be much more widespread than is commonly recognized, and may come to rival our currently favored ideas about toxicological dose responses confined to the linear and threshold representations used in risk assessment. Although hormesis-like biphasic dose responses were already well-established in chemical and radiation toxicology by the early decades of the 20th century, they were all but expunged from mainstream toxicology in the 1930s. The reasons may be found in a complex set of unrelated problems of which difficulties in replication of low-dose stimulatory responses resulting from poor study designs, greater societal interest in high-dose effects, linking of the concept of hormesis to the practice of homeopathy, and perhaps most crucially a complete lack of strong leadership to advocate its acceptance in the right circles. I believe that if hormesis achieves widespread recognition as a valid and valuable interpretation of dose-response results, we would expect an increase in the breadth of evaluations of the dose-response relationship which could be of great value in hazard and risk assessment as well as in future approaches to drug development and/or chemotherapeutics.

Evaluation of protective potentials of a potentized homeopathic drug, Chelidonium majus, during azo dye induced hepatocarcinogenesis in mice.

Several cytogenetical and enzymatic protocols were used to test if two microdoses of Chelidonium majus, namely Chelidonium-30 (Ch-30) and Chelidonium-200 (Ch-200), used as homeopathic drugs, showed anti-tumor activity and also favorably modulated genotoxic damages produced by an azo dye in mice at several intervals of fixation. Different sets of healthy mice were fed: (i) hepatocarcinogen, p-dimethylaminoazobenzene (p-DAB, initiator) + phenobarbital (PB, promoter), (ii) only p-DAB, (iii) only PB, and (iv) neither p-DAB nor PB (normal control). Mice fed with p-DAB + PB were divided into different sets that were also fed either Ch-30 (v) or Ch-200 (vi) or diluted alcohol (vii), the "vehicle" of the microdoses of Chelidonium. All mice of group (i), a few of group (ii) and group (vii) and none of groups (iii) and (iv) developed tumors in liver at the longer intervals of fixation. The frequencies of chromosome aberrations (CA), micronucleated erythrocytes (MN), mitotic index (MI) and sperm head abnormality (SHA) were much higher in groups (i) and (vii) mice than in groups (ii), (iii) and (iv) mice at all fixation intervals. However, in mice of both groups (v) and (vi), the frequencies of CA, MN, SHA were strikingly less than those of groups (i) and (vii), and moderately less than those of groups (ii) and (iii). Both Ch-30 and Ch-200 also modulated favourably some toxicity marker enzymes like acid and alkaline phosphatases, peroxidases, glutamate oxaloacetate and glutamate pyruvate transaminases in liver, kidney and spleen tissues of the carcinogen fed mice. The microdoses of Chelidonium having no visible ill effects of their own, may be strong candidates for use in delaying/protecting liver cancer.

Evaluation of the immunological cellular response of Cebus apella exposed to the carcinogen N-methyl-N-nitrosourea and treated with CANOVA®.

The immune response modifier Canova® is a homeopathic remedy indicated for patients with depressed immune system, since this drug appears to increase adaptive immunity and induce an immune response against multiple and severe pathological conditions, including cancer. We evaluated the pattern of immune cellular response in non-human primates of the species Cebus apella exposed to N-methyl-N-nitrosourea (MNU) with and without Canova®. Twelve animals were divided into four groups, with three animals each: negative control and three experimental groups, MNU-alone (35 days); MNU (35 days)-plus-Canova® (3 days) and Canova®-alone (3 days). The animals received MNU orally and Canova® by three intravenous injections. Evaluation of the cellular immune response was performed by immunophenotyping of T-lymphocytes (CD4(+), CD8(+)), B-lymphocytes and natural killer cells. Analysis was also performed of the cell cycle. Our results suggest an increase of T-lymphocytes (CD4(+)CD3(+)) only in the Canova® group, while in the MNU-plus-Canova® group only B-lymphocytes increased.

Two homeopathic remedies used intermittently provide additional protective effects against hepatotoxicity induced by carcinogens in mice.

The purpose of the study was to evaluate whether potentized cholesterinum (Chol) intermittently used with another homeopathic remedy, Natrum Sulphuricum (Nat Sulph) can provide additional benefits in combating hepatotoxicity generated by chronic feeding of carcinogens, p-dimethylaminoazobenzene (p-DAB), and phenobarbital (PB). Mice were categorized into subgroups: normal untreated (Gr-1); normal + alcohol "vehicle" (Alc) (Gr-2), 0.06% p-DAB +0.05% PB (Gr-3), p-DAB+PB+Alc (Gr-4), p-DAB+PB+Nat Sulph-30 (Gr-5), p-DAB+PB+Chol-200 (Gr-6), p-DAB+PB+Nat Sulph-30+Chol-200 (Gr-7), p-DAB+PB+Nat Sulph-200 (Gr-8), and DAB+PB+Nat Sulph-200+Chol-200 (Gr-9). Hepatotoxicity was assessed through biomarkers like aspartate and alanine aminotransferases (AST and ALT), acid and alkaline phosphatases (AcP and AlkP), reduced glutathione content (GSH), glucose 6-phosphate dehydrogenase (G6PD), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), and analysis of lipid peroxidation (LPO) at 30, 60, 90, and 120 days and antioxidant biomarkers like superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR) were assayed. Electron microscopic studies (scanning and transmission) and gelatin zymography for matrix metalloproteinases were conducted in liver. The feeding of the homeopathic drugs showed intervention in regard to the increased activities of AST, ALT, AcP, AlkP, GGT, LDH, and LPO and decreased activities of G6PD, SOD, CAT, GR, and GSH noted in the intoxicated mice, more appreciable in Groups 7 and 9. Thus, combined therapy provided additional antihepatotoxic and anticancer effects.

Toxicology rewrites its history and rethinks its future: giving equal focus to both harmful and beneficial effects.

This paper assesses how medicine adopted the threshold dose-response to evaluate health effects of drugs and chemicals throughout the 20th century to the present. Homeopathy first adopted the biphasic dose-response, making it an explanatory principle. Medicine used its influence to discredit the biphasic dose-response model to harm homeopathy and to promote its alternative, the threshold dose-response. However, it failed to validate the capacity of its model to make accurate predictions in the low-dose zone. Recent attempts to validate the threshold dose-response indicate that it poorly predicts responses below the threshold. The long marginalized biphasic/hormetic dose-response model made accurate predictions in these validation studies. The failure to accept the possibility of the hormetic-biphasic dose-response during toxicology's dose-response concept formative period, while adopting the threshold model, and later the linear no-threshold model for carcinogens, led toxicology to adopt a hazard assessment process that involved testing only a few very high doses. This created the framework that toxicology was a discipline that only studied harmful responses, ignoring the possibility of benefit at low doses by the induction of adaptive mechanisms. Toxicology needs to assess the entire dose-response continuum, incorporating both harmful and beneficial effects into the risk assessment process.