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Biomedical subjects

W G Flamm

Publications and source records attributed to W G Flamm.

At least 19 recordsLinked to original sources
PubMed1991

How sick a patient? Report of a workshop on cancer risk assessment.

A report by the U.S. Government Office of Management and Budget (OMB) criticized the way health, safety, and environmental regulation of potential cancer causing substances is conducted by federal agencies, especially the Environmental Protection Agency. Cancer risk assessment--this report indicates--is governed by arbitrary policy assumptions and procedures improperly disguised as scientific and is designed to overestimate risk. Unwarranted economic burdens of ensuing regulation may then adversely affect standards of living and ultimately the very health and longevity that regulation is presumed to safeguard. An interdisciplinary workshop generally agreed with the OMB position and sharpened criticism of the procedures and scientific pretensions in the regulation of potential carcinogens. Various options for change were discussed, although it was felt that the success of detailed remedies would require a wider political, administrative, and scientific discourse.

Carcinogens↗
PubMed1991

The human relevance of the renal tumor-inducing potential of d-limonene in male rats: implications for risk assessment.

The monoterpene d-limonene is a naturally occurring chemical which is the major component in oil of orange. Currently, d-limonene is widely used as a flavor and fragrance and is listed to be generally recognized as safe (GRAS) in food by the Food and Drug Administration (21 CFR 182.60 in the Code of Federal Regulations). Recently, however, d-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to d-limonene causes a significant incidence of renal tubular tumors exclusively in male rats. Although d-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of d-limonene may raise some concern regarding the safety of d-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of d-limonene results from the accumulation of a protein, alpha 2u-globulin, in male rat kidney proximal tuble lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with alpha 2u-globulin. However, none of these proteins, including the mouse equivalent of alpha 2u-globulin, can produce this toxicity, indicating a unique specificity for alpha 2u-globulin. With chronic exposure to d-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensatory cell proliferation. Both d-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in in vitro mutagenicity screens. Therefore, the toxicity-related renal cell proliferation is believed to be integrally involved in the carcinogenicity of d-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The scientific data base demonstrates that the tumorigenic activity of d-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of d-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that alpha 2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both d-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Critical assessment of carcinogenic risk policy.

Fact. Cancer is a relatively common yet greatly feared disease. Belief. The concept that cancer is largely preventable is widely held by advocate groups, the press, and Congress. Belief. The concept that carcinogens at any level of exposure pose a significant cancer risk to human is widely believed by the public. Fact. In contrast to this belief, carcinogens are now known to be widespread in the environment and that virtually all substances are contaminated with carcinogens at some albiet low level. Fact. The solution to the ubiguitous presence of carcinogens cannot be solved by regulatory fiat. Fact. Often the only viable solution to regulating carcinogens is setting maximum levels of acceptable exposure (tolerances). Belief. In U.S. society, the process of establishing tolerances must be conducted in the open, providing adequate opportunity for public comment. Fact. The courts will sustain regulatory agency decisions about risks only if the administrative procedures used comply with the Administrative Procedures Act and if the technical methodology used is in good standing. Fact. For the method to be in good standing it cannot be a recent invention created after the fact to solve the issue at hand but must instead be a procedure that is claimed to be generally applicable to determining or estimating cancer risk. Belief. QRA should be an orderly procedure or process by which cancer risk estimations are conducted in an unbiased manner. As such it is fundamentally acceptable to the courts for resolving disputes. Fact. However, because QRA is dependent upon a large number of assumptions and because regulatory agencies feel compelled to act in a conservative, risk-adverse manner, risk estimates are often criticized for being over stated. Belief. To make risk estimates more realistic, data or facts must substitute for worst case assumptions. Fact. This process of substituting scientific facts for assumptions is occurring but it is expensive, time consuming, and not always possible. Nevertheless, it constitutes a major opportunity for improving the process by which risk estimates are made.

Animals↗
PubMed1989

FDA procedures and policies to estimate risks of injury to the male reproductive system.

Two decades ago, the Food and Drug Administration (FDA) undertook a testing and research program to study and assess the mutagenic properties of so-called "Generally Recognized as Safe" (GRAS) substances which have a long history of use in food. Initially, the program employed three highly regarded mutagenicity tests; the host mediated assay, somatic cell cytogenetics, and the dominant lethal test. Only the latter measures male germ cell events. Eventually, research and testing results revealed major problems in the deployment of these tests for such purposes. A new approach involving a three tiered system was instituted in which the first tier was a relatively inexpensive pre-screen ostensibly capable of detecting any and all potential mutagens. For reasons of economy, this pre-screen used micro-organisms. The objective of the second tier was to determine if substances positive in the first tier of tests would be mutagenic for higher organisms. Gene mutation in mammalian cells in culture, gene plus chromosomal mutation in Drosophila and heritable translocation in male mice were used for this purpose. The final tier was intended to assess the quantitative risk of mutation in mammals and depended entirely upon genetic studies in animals. Again, the heritable translocation test would be used as well as the specific locus test in mice. At the same time, efforts were made to refine and improve the usefulness of the dominant lethal and the heritable translocation test for toxicological purposes. More recently, studies have been undertaken to develop a practical test for nondisjunction in male germ cells. Currently, standard test requirements for food additive approval include only short-term in vitro mutagenicity tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Beryllium: laboratory evidence.

Beryllium-containing compounds have been studied extensively and have been known to be carcinogenic in animals since 1946. Beryllium salts and alloys were among the first nonradioactive, inorganic substances shown to induce osteogenic sarcoma in experimental animals. Beryllium-containing compounds have been demonstrated to be powerful pulmonary carcinogens in rats. To date, these compounds do not appear to be mutagenic, leaving open the question of their mechanism of action.

Animals↗
PubMed1985

Nitrates: laboratory evidence.

Neither nitrate nor nitrite per se has been demonstrated to produce cancer in experimental animals. The potential carcinogenicity of either of these substances would appear to derive from their involvement in the production of carcinogenic N-nitroso compounds. The extent to which such compounds form has been the subject of numerous studies.

Animals↗
PubMed1978

Heritable translocation test on random-bred mice after prolonged triethylenemelamine treatment.

Heritable translocation and dominant lethal tests were conducted with random-bred Swiss albino male mice. The animals were provided drinking water containing triethylenemelamine (TEM) for 4 weeks, and were then mated for 3 successive weeks for analysis of dominant lethality and production of F1 progeny. Potential translocation carriers among F1 males were selected after two breedings and confirmed by cytogenetic analysis. Translocation heterozygotes were obtained in offspring of the TEM-treated groups, but not in the control groups. In F1 males produced from the first week of mating, the frequencies of translocations were 0, 1.78 6.2 and 10.0% for the control group and groups receiving TEM at 0.0125, 0.025 and 0.050 mg/kg/day, respectively, and in those produced from the third week of mating, the values were 0 and 2.1%, respectively, for the control group and the group receiving TEM at 0.050 mg/kg/day. F1 males from the second week of mating were not studied for the induction of heritable translocations. TEM-induced dominant lethality and heritable translocations were most prominent in the first week of mating after 4 weeks of treatment. In addition, heritable translocations appeared to be a more sensitive endpoint than dominant lethal mutations for the measurement of mutagenic effects of TEM.

Animals↗
PubMed1975

Legislative and technical aspects of mutagenicity testing.

A brief account is given of the history of the legislative acts that give responsibility to the U.S. Food and Drug Administration (FDA) for ensuring the safety of foods, drugs, and cosmetics. Within the present legislative framework the FDA has the authority to impose regulations which are designed to ensure the safety of all foods, drugs, and cosmetics. The existing legislative authority is adequate for this purpose; however, the difficulty lies instead with technology and the inadequacy of scientific perspective in the emerging area of mutagenicity testing. Earlier efforts in development of mutagenicity screening systems culminated only a few years ago in the proposal to use the host-mediated assay, somatic cell cytogenetics, and dominant lethal tests collectively. Subsequent research efforts indicated that there were serious practical and scientific deficiencies in using this approach. More recently a new proposal, the tier system, has been suggested as an alternative measure. The proposed tier system at FDA consists of three testing levels of increasing complexity. The first tier is an initial screening effort using techniques having maximum sensitivity that are also useful for large-scale, rapid testing. The second tier is designed to identify and confirm that the presumptive mutagens detected in the first tier are truly mutagenic for higher organisms, most especially, for mammals. The third tier would be devoted to explicit genetic tests in mammals designed to ascertain the imposed risk to man by the introduction of a mutagen in our environment. The FDA is currently involved in a number of research activities in the area of mutagenicity safety screening which will explore the adequacies and possible deficiencies of the tier system approach. These efforts are described for our in-house activities, our contract activities, and our cooperative and collaborative activities with other government agencies and institutions.

Animals↗
PubMed1975

Test systems for assessing mutagenic potential of chemical substances.

The first report that certain chemicals have the potential of inducing heritable effects (mutation) appeared in the mid-1940's. Two decades passed before this and subsequent observations were translated into a concern that some of the chemicals to which we are exposed may constitute a hazard to man's genetic material and hence a threat to future generations of individuals. Such concern has led to the gradual evolution of the newest subdiscipline of toxicology, genetic toxicology. This subdiscipline is still young and faces many challenges in terms of developing sound toxicologic approaches for meeting specific evaluation needs in the interest of public health. This paper describes the current status of efforts in genetic toxicology and the types of steps which must be taken in order to begin to meet the needs and requirements of regulatory agencies.

Biotransformation↗