This paper will introduce a new model for Linear Logic, the IE model . Intuitively the model assumes there is a global environment which is divided up into an internal resource and an external resource. Such an assumption makes for an elementary definition of linear negation. The model results in a fairly natural semantics for the multiplicative operators and the constants of Linear Logic. A particular example of the model is given which gives a proper technical account of the cigarette (...) example. (shrink)

Brazil is the biggest market for pesticides in the world. In the registration process, a pesticide must be authorized by the Institute of the Environment, Health Surveillance Agency and Ministry of Agriculture. Evaluations follow a package of toxicological studies submitted by the companies and also based on the Brazilian law regarding pesticides. We confronted data produced by private laboratories, submitted to the Institute of the Environment for registration, with data obtained from scientific databases, corresponding to mutagenicity, carcinogenicity and teratogenicity of (...) pesticides. All studies submitted by the companies were carried out by private laboratories. From 247 pesticide formulations analyzed, none showed positive results for mutagenicity, carcinogenicity or teratogenicity. From 574 articles in the scientific literature, 84% published by public laboratories showed positive results, while 79% of those showing negative results came from private laboratories. There is an ethical concern about a conflict of interest between public/independent laboratories and private laboratories that produce data for registering pesticides. We demonstrated that there is a clear contradiction between public and private laboratories. Brazilian regulatory authorities have approved the registration of pesticides based almost exclusively on the monographs provided by the pesticide industry, because the use of scientific articles or information from the independent literature is strongly belittled by the industry. Pesticide companies argue that scientific articles cannot be trusted. Also, according to the industry, pesticide registration cannot be refused based on results from scientific articles. Thus, the registration of pesticides with mutagenic, carcinogenic and teratogenic risks has been approved in Brazil. (shrink)

Book reviewed in this article: PBB: An American Tragedy. By Edwin Chen. The Law and Policy of Toxic Substances Control: A Case Study of Vinyl Chloride. By David D. Doniger.

It is argued that neoliberal political ideology has redefined the regulatory state to have greater convergence of interests and goals with the pharmaceutical industry than previously, particularly regarding acceleration and cost reduction of drug development and regulatory review. Consequently, the pharmaceutical industry has been permitted to set the agenda about how shorter term and cheaper alternative carcinogenicity testing systems are investigated for validity. The authors contend that, with the tacit approval of the neoliberal regulatory state, the commercial interests of the (...) pharmaceutical industry framed the process and interpretation of validating these new test systems, thereby influencing what counts as knowledge about the carcinogenic status of new pharmaceuticals. While such alternative tests were occasioned by “molecularization,” the framing of their validation was not determined by technoscientific logic or a lack of standards of validation, but by the sociopolitical goals of the controlling institutions. Indeed, a different validation process could have been conducted had the priority been to develop carcinogenicity testing in the interests of public-health protection. While the resulting validation indicated that the short-term alternative tests posed small risks to the commercial interests of pharmaceutical firms, they provided little reassurance that patients would not be exposed to greater risks than before from undetected carcinogens. (shrink)

Recent work in science and technology studies has looked at how chemical industries manufacture doubt about the toxicity of their products and manage to establish their scientific views in the field of international regulations on toxic substances. Rather than examining yet another “victory” for the industry, this article analyzes the deployment of a “pro-industrial” scientific position, punctuated mainly by failure and opposition. This trajectory is tracked through the analysis of several data sets: archives, scientific documentation, and sociological interviews. The first (...) part of the article charts the development of a biochemical concept, “peroxisome proliferation,” within an academic subfield and its subsequent appropriation by certain industrial parties who used it as a defensive weapon for their commercial interests. Through the example of the International Agency for Research on Cancer and its network of interdependent institutions, the article goes on to analyze the multiple attempts of chemical industry players to establish their interpretation of the concept within the regulatory bodies for carcinogenic substances. The study of such systems of sociological interdependence shows that a full analysis of the “doubt manufacturing” requires an examination not only of the manufacturing process but also of the reception of the ideas produced. (shrink)

I argue that although the judgments required to reach statistical risk assessments may reflect policy values, it does not follow that the task of evaluating whether a given risk assessment is warranted by the evidence need also be imbued with policy values. What has led many to conclude otherwise, I claim, stems from misuses of the statistical testing methods involved. I set out rules for interpreting what specific test results do and do not say about the extent of a given (...) risk. By providing a more objective understanding of the evidence, such rules help in adjudicating conflicting risk assessments. To illustrate, I consider the risk assessment conflict at the EPA concerning the carcinogenicity of formaldehyde. (shrink)

We aim to build intelligent systems which can reason autonomously about the carcinogenicity of chemicals. Scientific debates in this area draw on evidence from multiple, and often conflicting sources, both theoretical and experimental, and participants use various modes of inferential reasoning. In seeking to automate such reasoning, we have first articulated precisely the multiple modes of inference used when an assertion of human carcinogenicity is made from experimental animal evidence. Because such inferences are often contested, scientific debate in this domain (...) can be vigorous. To model such debates, we propose the use of a form of dialectical argumentation, drawing on Habermas' philosophy of Discourse Ethics [9] and Pera's philosophy of science [18]. The resulting formalism permits the representation of uncertainty and disagreement regarding the modes of inference used, as well as the claims being asserted. (shrink)

Government agencies and private risk assessors use (quasi) scientific risk assessment procedures to try to estimate or predict risk to human health or the environment that might result from exposure to toxic substances in order to take steps to prevent such risks from arising or to eliminate the risks if they already exist. In this paper I discuss several ways in which the "science" of carcinogen risk assessment differs from ordinary scientific enterprises. I also consider several ways in which normative (...) policy considerations infect this regulatory science. Scientists, philosophers of science, moral philosophers and policy makers should address these issues forthrightly in order to serve better the aims of science and regulation. (shrink)

Ethicists widely accept the notion that scientists have moral responsibilities to benefit society at large. The dissemination of scientific information to the public and its political representatives is central to many of the ways in which scientists serve society. Unfortunately, the task of providing information can often give rise to moral quandaries when scientific experts participate in politically charged debates over issues that are fraught with uncertainty. This paper develops a theoretical framework for an “ethics of expertise” (EOE) based on (...) the notion that scientists have responsibilities to provide information in a way that promotes autonomous decision-making on the part of the public and its representatives. Moreover, insofar as the principle of informed consent has developed in biomedical ethics as a way for physicians to promote autonomous decision-making on the part of their patients, this paper suggests that the informed-consent concept may suggest a set of criteria and guidelines that can help scientists to fulfill their similar ethical responsibilities to the public. In order to illustrate how the resulting EOE could provide practical guidance for scientific experts, the paper examines a case study involving the dissemination of information about the low-dose biological effects of toxic chemicals and carcinogens. (shrink)

The accumulation of potentially toxic elements (PTEs) has raised public awareness due to harmful contamination to both human and marine creatures. This study was designed to determine the concentration of copper (Cu), zinc (Zn), cadmium (Cd), and nickel (Ni) in the intestine, kidney, muscle, gill, and liver tissues of local commercial edible fish, fourfinger threadfin (Eleutheronema tetradactylum), and black pomfret (Parastromateus niger) collected from Morib (M) and Kuala Selangor (KS). Among the studied PTEs, Cu and Zn were essential elements to (...) regulate body metabolism with certain dosages required while Cd and Ni were considered as non-essential elements that posed chronic and carcinogenic risk. The concentration of PTEs in fish tissue samples was analyzed using flame atomic absorption spectrometry (F-AAS). By comparing the concentration of PTEs in fish tissues as a bioindicator, the environmental risk of Morib was more serious than Kuala Selangor because both fish species collected from Morib resulted in a higher PTEs concentration. For an average 62 kg adult with a fish ingestion rate (FIR) of 0.16 kg/person/day in Malaysia, the estimated weekly intake (EWI) of Cd from the consumption of E. tetradactylum (M: 0.0135 mg/kg; KS: 0.0134 mg/kg) and P. niger (M: 0.0140 mg/kg; KS: 0.0132 mg/kg) had exceeded the provisional tolerable weekly intake (Cd: 0.007 mg/kg) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and oral reference dose (ORD) values of Cd (0.001 mg/kg/day) as provided by the United States Environmental Protection Agency (USEPA) regional screening level, thus it posed chronic risks for daily basis consumption. Besides, the value of the carcinogenic risk of Cd (0.7−3 to 0.8−3) and Ni (0.5−3 to 0.6−3) were in between the acceptable range (10−6 to 10−4) of the health index that indicates a relatively low possibility cancer occurrence to the consumers in both Morib and Kuala Selangor. This study recommended FIR to be 0.80 kg/person/day to reduce the possibility of posing chronic and carcinogenic risks while at the same time obtaining the essential nutrients from the fish. (shrink)

The International Agency for Research on Cancer (IARC) is an organization which seeks to identify the causes of human cancer. Per agent, such as betel quid or Human Papillomaviruses, they review the available evidence deriving from epidemiological studies, animal experiments and information about mechanisms (and other data). The evidence of the different groups is combined such that an overall assessment of the carcinogenicity of the agent in question is obtained. In this paper, we critically review the IARC’s carcinogenicity evaluations. First (...) we show that serious objections can be raised against their criteria and procedures – more specifically regarding the role of mechanistic knowledge in establishing causal claims. Our arguments are based on the problem of confounders, of the assessment of the temporal stability of carcinogenic relations, and of the extrapolation from animal experiments. Then we address a very important question, viz. how we should treat the carcinogenicity evaluations that were based on the current procedures. After showing that this question is important, we argue that an overall dismissal of the current evaluations would be too radical. Instead, we argue in favour of a stepwise re-evaluation of the current findings. (shrink)

This article tracks the transformation of beagle dogs from a common breed in mid-twentieth century American laboratories to the de jure standard in global toxicological research by the turn of the twenty-first. The breed was dispersed widely due to the expanding use of dogs in pharmacology in the 1950s and a worldwide crisis around pharmaceutical safety following the thalidomide scandal of the 1960s. Nevertheless, debates continued for decades over the beagle’s value as a model of carcinogenicity, even as the dogs (...) became legislated stand-ins for human beings in multiple countries. Situating beagles as a biocommodity, the article calls for more sustained attention to the “political economy” of laboratory organism breeding, use, and production. The story of American commercial breeder Marshall Farms offers insight into the role of for-profit companies in contemporary laboratory animal provision, as the article makes a case for the value of a global perspective on transnational corporations as key sites of scientific practice and collaboration. (shrink)

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert Advisory Group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since (...) the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs Programme. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating and integrating evidence to identify causes of human cancer. The advancements adopted include strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention. (shrink)

ln the Netherlands, as in other Western countries, there is a great time lag between the evidence of the carcinogenicity of asbestos (1949) and the launching of first legislation that reduces the occupational exposure (1971) and finally, the complete ban of the production and application of asbestos (1993). So, between 1949 and 1970 there was a serious health risk while effective protective regulations were lacking. This implied a serious ethical dilemma for occupational health professionals: according to their code of ethics, (...) they ought to contribute to a safe and healthy working environment while companies are not strictly obliged to do so. This study explores retrospectively the position of health and safety professionals with regard to asbestos between 1930 and 1990; specifically with respect to the prevention of harmful health effects for exposed workers, which is a central value in their professional ethics. It turns out that the associations of safety and health professionals did not promulgate any position on the prevention of harm due to asbestos. Nor did the uncertainty about the health impact of asbestos obviously cause an ethical dilemma for individual professionals. Professionals were usually involved in discussions on diagnostic methods of asbestos exposure in the human body (X-ray or detection in sputum), the existence of safe limits, the scientific basis of risk assessment and effective prevention strategies. Only a single professional was seeking attention to the severe health risks and advocated for preventive action. (shrink)

One way to do socially relevant investigations of science is through conceptual analysis of scientific terms used in special-interest science (SIS). SIS is science having welfare-related consequences and funded by special interests, e.g., tobacco companies, in order to establish predetermined conclusions. For instance, because the chemical industry seeks deregulation of toxic emissions and avoiding costly cleanups, it funds SIS that supports the concept of "hormesis" (according to which low doses of toxins/carcinogens have beneficial effects). Analyzing the hormesis concept of (...) its main defender, chemical-industry-funded Edward Calabrese, the paper shows Calabrese and others fail to distinguish three different hormesis concepts, H, HG, and HD. H requires toxin-induced, short-term beneficial effects for only one biological endpoint, while HG requires toxin-induced, net-beneficial effects for all endpoints/responses/subjects/ages/conditions. HD requires using the risk-assessment/regulatory default rule that all low-dose toxic exposures are net-beneficial, thus allowable. Clarifying these concepts, the paper argues for five main claims. (1) Claims positing H are trivially true but irrelevant to regulations. (2) Claims positing HG are relevant to regulation but scientifically false. (3) Claims positing HD are relevant to regulation but ethically/scientifically questionable. (4) Although no hormesis concept (H, HG, or HD) has both scientific validity and regulatory relevance, Calabrese and others obscure this fact through repeated equivocation, begging the question, and data-tri mm ing. Consequently (5) their errors provide some undeserved rhetorical plausibility for deregulating low-dose toxins. (shrink)

Exocyclic DNA adducts are mutagenic lesions that can be formed by both exogenous and endogenous mutagens/carcinogens. These adducts are structurally analogs but can differ in certain features such as ring size, conjugation, planarity and substitution. Although the information on the biological role of the repair activities for these adducts is largely unknown, considerable progress has been made on their reaction mechanisms, substrate specificities and kinetic properties that are affected by adduct structures. At least four different mechanisms appear to have (...) evolved for the removal of specific exocyclic adducts. These include base excision repair, nucleotide excision repair, mismatch repair, and AP endonuclease‐mediated repair. This overview highlights the recent progress in such areas with emphasis on structure–activity relationships. It is also apparent that more information is needed for a better understanding of the biological and structural implications of exocyclic adducts and their repair. BioEssays 26:1195–1208, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The pigment melanin is found in all living kingdoms and in many different structures and forms. When its various functions are examined separately, its behaviors seem disparate and conflicting. It has a clear role in camouflage and sexual display. Other major roles are examined critically. It can act as a sun screen but is not a very effective one. It can also scavenge active chemical species, but this, too, is not done very effectively. It produces active radicals that can damage (...) DNA. It binds to drugs in ways that are either beneficial or deleterious. Aside from camouflage, its other roles can be brought together by a unifying hypothesis as first proposed by Proctor and McGinness nearly 20 years ago. Melanin is envisaged as an energy transducer with the properties of an amorphous semiconductor. It can absorb many different types of energy and dissipate them in the form of heat. However, if the energy input is too great, the output can be expressed in the form of activated chemical species that can damage cellular macromolecules resulting in cell death, mutations and cancer. The protective aspect of melanin in dark skin is seen as resulting from its high concentration and its confinement to ellipsoidal and densely packed organelles that can effectively shield the nucleus. In light skin, its radical nature is seen as potentially participating in the carcinogenic process, particularly when overwhelmed by intense episodes of sunburn. (shrink)

This article traces the different classifications of diesel emissions either as “safe” or as “hazardous” in the US and in West Germany between 1977 and 1995. It argues that the environmental regulation of diesel emissions was a political threshold. It contributes to our general understanding of how politicians, environmental lobbyists, scientists, and engineers constructed the standards and norms that defined the “safe” limit of environmental pollutants. After discussing how diesel emissions came under review as a potential carcinogen, I will show (...) that the coding as “safe” or as “hazardous” resulted from negotiations that were entirely dependent on the temporal, geographical, and intellectual contexts in which diesel technology, scientific research on their emissions, and political regulation were embedded. In particular, I trace the differences in German and US regulatory policy. While US regulation relied more on epidemiology that provided only weak data on the carcinogenicity of diesel particulates in the early 1980s, German government agencies tended to base their policy around the mid-1980s more on the results of animal tests and shortly afterwards also on epidemiology. Furthermore, the article reveals how US and German automakers tried to foster doubt on the carcinogenicity of diesel emissions and how their approaches differed and shifted. Thereby, it sheds light on the triangular relationship between technology, science, and politics in regulatory processes by analyzing the different roles of the state, automakers, scientists, and environmental agencies in Germany and in the United States. (shrink)

We hear that a glass of red wine prolongs life, that alcohol is a carcinogen, that pregnant women should drink not a drop of alcohol. Major medical journals first claimed that hormone replacement therapy reduces the risk of heart disease, then reversed themselves and said it increases the risk of heart disease. What are the effects caused by consuming alcohol or by receiving hormone replacement therapy? These are causal questions, questions about the effects caused by treatments, policies or preventable exposures. (...) Some causal questions can be studied in randomized trials, in which a coin is flipped to decide the treatment for the next experimental subject. Because randomized trials are not always practical, nor always ethical, many causal questions are investigated in non-randomized observational studies. The reversal of opinion about hormone replacement therapy occurred when a randomized clinical trial contradicted a series of earlier observational studies. Using minimal mathematics - high school algebra and coin flips -- and numerous examples, Observation and Experiment explains the key concepts and methods of causal inference. Examples of randomized experiments and observational studies are drawn from clinical medicine, economics, public health and epidemiology, clinical psychology and psychiatry. (shrink)

Humans accumulate porphyrins in the body mostly during the course of porphyrias, diseases caused by defects in the enzymes of the heme biosynthesis pathway and that produce acute attacks, skin lesions and liver cancer. In contrast, some wild mammals and birds are adapted to accumulate porphyrins without injurious consequences. Here we propose viewing such physiological adaptations as potential solutions to human porphyrias, and suggest certain wild animals as models. Given the enzymatic activity and/or the patterns of porphyrin excretion and accumulation, (...) the fox squirrel, the great bustard and the Eurasian eagle owl may constitute overlooked models for different porphyrias. The Harderian gland of rodents, where large amounts of porphyrins are synthesized, presents an underexplored potential for understanding the carcinogenic/toxic effect of porphyrin accumulation. Investigating how these animals avoid porphyrin pathogenicity may complement the use of laboratory models for porphyrias and provide new insights into the treatment of these disorders. (shrink)

The discovery by Hans Spemann of the “organizer” tissue and its ability to induce the formation of the amphibian embryo's neural tube inspired leading embryologists to attempt to elucidate embryonic inductions’ underlying mechanism. Joseph Needham, who during the 1930s conducted research in biochemical embryology, proposed that embryonic induction is mediated by a specific chemical entity embedded in the inducing tissue, surmising that chemical to be a hormone of sterol-like structure. Along with embryologist Conrad H. Waddington, they conducted research aimed at (...) the isolation and functional characterization of the underlying agent. As historians clearly pointed out, embryologists came to question Needham's biochemical approach; he failed to locate the hormone he sought and eventually abandoned his quest. Yet, this study finds that the difficulties he ran into resulted primarily from the limited conditions for conducting his experiments at his institute. In addition, Needham's research reflected the interests of leading biochemists in hormone and cancer research, because it offered novel theoretical models and experimental methods for engaging with the function of the hormones and carcinogens they isolated. Needham and Waddington were deterred neither by the mounting challenges nor by the limited experimental infrastructure. Like their colleagues in hormone and cancer research, they anticipated difficulties in attempting to establish causal links between complex biological phenomena and simple chemical triggering. (shrink)

The discovery by Hans Spemann of the “organizer” tissue and its ability to induce the formation of the amphibian embryo’s neural tube inspired leading embryologists to attempt to elucidate embryonic inductions’ underlying mechanism. Joseph Needham, who during the 1930s conducted research in biochemical embryology, proposed that embryonic induction is mediated by a specific chemical entity embedded in the inducing tissue, surmising that chemical to be a hormone of sterol-like structure. Along with embryologist Conrad H. Waddington, they conducted research aimed at (...) the isolation and functional characterization of the underlying agent. As historians clearly pointed out, embryologists came to question Needham’s biochemical approach; he failed to locate the hormone he sought and eventually abandoned his quest. Yet, this study finds that the difficulties he ran into resulted primarily from the limited conditions for conducting his experiments at his institute. In addition, Needham’s research reflected the interests of leading biochemists in hormone and cancer research, because it offered novel theoretical models and experimental methods for engaging with the function of the hormones and carcinogens they isolated. Needham and Waddington were deterred neither by the mounting challenges nor by the limited experimental infrastructure. Like their colleagues in hormone and cancer research, they anticipated difficulties in attempting to establish causal links between complex biological phenomena and simple chemical triggering. (shrink)

Promyelocytic leukaemia nuclear bodies (PML NBs) are generally present in all mammalian cells, and their integrity correlates with normal differentiation of promyelocytes. Mice that lack PML NBs have impaired immune function, exhibit chromosome instability and are sensitive to carcinogens. Although their direct role in nuclear activity is unclear, PML NBs are implicated in the regulation of transcription, apoptosis, tumour suppression and the anti‐viral response. An emerging view is that they represent sites where multi‐subunit complexes form and where post‐translational modification (...) of regulatory factors, such as p53, occurs in response to cellular stress. Following DNA damage, several repair factors transit through PML NBs in a temporally regulated manner implicating these bodies in DNA repair. We propose that PML NBs are dynamic sensors of cellular stress, which rapidly disassemble following DNA damage into large supramolecular complexes, dispersing associated repair factors to sites of damage. The dramatically increased total surface area available would enhance interactions between PML‐associated factors regulating DNA repair and apoptosis. BioEssays 26:963–977, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Rho proteins belong to the small GTPases superfamily. They function as molecular switches that, in response to diverse stimuli, control key signaling and structural aspects of the cell. Although early studies proposed a role for Rho GTPases in cellular transformation, this effect was underestimated due to the fact that no genetic mutations affecting Rho‐encoding genes were found in tumors. Recently, it has become evident that Rho GTPases participate in the carcinogenic process by either overexpression of some of the members of (...) the family with oncogenic activity, downmodulation of other members with suggested tumor suppressor activity, or by alteration of upstream modulators or downstream effectors. Thus, alteration of the levels of expression of different members of the family of Rho GTPases has been detected in many types of human tumors leading to a great interest in the cellular effects elicited by these oncoproteins. This essay reviews the current evidence of dysregulation of Rho signaling by overexpression in human tumors. BioEssays 27:602–613, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Exposure of man to chemical agents can occur intentionally, as in the treatment of disease, or inadvertently because the environment contains a wide range of synthetic or naturally occurring chemicals. The alkylating agents are a diverse group of compounds (Fig. 1) and comprise a good example of such xenobiotics, since much is known about their occurrence, and their biological effects include carcinogenicity, mutagenicity, toxicity and teratogenicity.Exposure to potentially carcinogenic alkylating agents such as nitrosamines may occur occupationally, from cigarette smoke, from (...) certain foodstuffs and even endogenously through the ingestion of the appropriate precursor chemicals.1 At the other extreme, the cytotoxic effects of agents such as the chloroethylating nitrosamides or mustards have been exploited in the design of certain antitumour drugs.2 The effectiveness of antitumour agents and the other, mostly adverse, biological effects of alkylating agents have been ascribed to their ability to damage cellular macromolecules, in particular DNA. This review concentrates on investigations carried out over the past two years on the role of DNA damage in carcinogenesis, but we shall see how recent advances in this area of research have also led to a better understanding of the mechanisms of the cytotoxic effects of alkylating antitumour agents. (shrink)

The DNA in human cells is continuously undergoing damage as consequences of both endogenous processes and exposure to exogenous agents. The resulting structural changes can be repaired by a number of systems that function to preserve genome integrity. Most pathways are multicomponent, involving incision in the damaged DNA strand and resynthesis using the undamaged strand as a template. In contrast, O6-alkylguanine-DNA alkyltransferase is able to act as a single protein that reverses specific types of alkylation damage simply by removing the (...) offending alkyl group, which becomes covalently attached to the protein and inactivates it. The types of damage that ATase repairs are potentially toxic, mutagenic, recombinogenic and clastogenic. They are generated by certain classes of carcinogenic and chemotherapeutic alkylating agents. There is consequently a great deal of interest in this repair system in relation to both carcinogenesis and cancer chemotherapy. BioEssays 24:255–266, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10063. (shrink)

While providing people with the same nicotine that forms the basis of their physical addiction, there is no available evidence that electronic nicotine delivery systems have carcinogenic eff...

When the Toxic Substances Control Act was passed by the US Congress in 1976, its advocates pointed to new generation of genotoxicity tests as a way to systematically screen chemicals for carcinogenicity. However, in the end, TSCA did not require any new testing of commercial chemicals, including these rapid laboratory screens. In addition, although the Environmental Protection Agency was to make public data about the health effects of industrial chemicals, companies routinely used the agency’s obligation to protect confidential business information (...) to prevent such disclosures. This paper traces the contested history of TSCA and its provisions for testing, from the circulation of the first draft bill in the Nixon administration through the debates over its implementation, which stretched into the Reagan administration. The paucity of publicly available health and environmental data concerning chemicals, I argue, was a by-product of the law and its execution, leading to a situation of institutionalized ignorance, the underside of regulatory knowledge. (shrink)

The biological effects of low doses of toxic and carcinogenic chemicals are currently a matter of significant scientific controversy. This paper argues that philosophers of science can contribute to alleviating this controversy by examining it with the aid of a novel account of scientific anomaly. Specifically, analysis of contemporary research on chemical hormesis (i.e., alleged beneficial biological effects produced by low doses of substances that are harmful at higher doses) suggests that scientists may initially describe anomalous phenomena in terms of (...) multiple distinct "characterizations," each of which is compatible with current empirical evidence. By focusing attention on this feature of scientific anomalies, philosophers of science can alleviate the controversy over low-dose chemical effects in at least two ways: (1) they can pinpoint the significant ways in which particular characterizations frame the controversy, and (2) they can identify the methodological value judgments at stake in researchers' choice of characterizations. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:240 Feminist Studies 45, no. 1. © 2019 by Mary Anna Evans Mary Anna Evans Personal Continuum The scent of gasoline is neither attractive nor repulsive. It falls somewhere on the continuum between. It is medicinal, but without the acrid bitterness of medicine. It draws children like a drug, but only when their parents aren’t hovering to warn of danger. Adults know about fire and poisoning and long-range carcinogenic (...) doom. Children only know that the odor around gas pumps smells naughty and fun, until their lips open and the flavor of petroleum turns their stomachs. Why do some things smell so much better than they taste? Gasoline, unlike honey, draws humans but not flies. Sarah was not thinking of fire, poisoning, or doom when she fitted the long metal nozzle into the mouth of her car’s fuel tank. She was trying not to think at all, though the customary thoughts slipped in. None of them were about gasoline. The pump’s air pollution control system was working well but not perfectly, so it took a moment for the odor to reach her nose. Her body roused and snarled at her. The baby. What are you thinking? If you breathe those fumes, what will they do to the baby? A moment passed while her body checked itself, remembering what it already knew. There was no baby. Where is the baby? Mary Anna Evans 241 The frantic voice didn’t echo between her ears. It had nothing to do with her brain at all. It was more than thought. It came from a place deeper than thought, and it wasn’t hers. Her body said things she didn’t want to say, and it needed things she didn’t need. Her body wanted things that were not good for her. Again, Where is the baby? And then, the darker question. What did you do? “Nothing,” she said aloud, since there was no one to hear. I didn’t do anything but bleed. I’m still bleeding. She resisted the instinct to clap her hands over her ears to shut out the voice that couldn’t be shut out. Her defiant hold on the nozzle kept her upright. She listened to the rhythmic throb of the pump. Refusing to turn her face from the gasoline’s stench, she opened her mouth and let the fumes seep in. * * * “Hello, sweetheart,” Frederick said as he came in the door. His peck on the cheek didn’t linger, so Sarah knew there would be no more expressions of affection that day. He had read in a self-help book that it was important for couples to use terms of endearment as a form of bonding. Physical displays of affection were important, too, or so said the self-affirmed relationship expert who wrote the book. In public, displays of affection affirmed the pair bond. In private, even a quick smooch forced men and women to secrete an attachment chemical called oxy-whatever. Oh, hell. She was a chemist. She knew what oxytocin was. She was just mystified by the notion of reading a book to find out how to get some. He turned away and went into the kitchen to fetch the marinating chicken. He always grilled when it was his night to cook. She had come to wonder whether modern men were drawn to cook with fire by an ageold hunter instinct, or whether they were attracted to an activity that put a well-insulated exterior wall between them and the women who remained inside to toss the salads. All across America, every warm summer night, lonely women toss salads and hope for romance. His head poked in the back door. “I bought slivered almonds and croutons.” 242 Mary Anna Evans Her “Thanks for remembering, sweetheart,” bounced off the closing door. Shit. She could have spared herself that soulless term of endearment. Leaving the lettuce in the refrigerator, she thrust her soapy hands under warm running water, because even thinking the word “shit” made the idea of handling raw food appalling. Her body, which had forgotten again that she’d lost the baby, approved of her caution. She guarded her thoughts against disturbing its... (shrink)

Current pharmacopoeias invariably refer to a category of ‘alkylating drugs’, still among the most widely used in cancer chemotherapy. They are described as acting through their ability to damage DNA, thus interfering with cell replication. Unfortunately, this mode of action implicates these drugs as carcinogens. Thus the early studies recalled in this essay proved to be relevant to our understanding of both the main problems with which cancer research concerns itself: the causation of cancer and possible methods of treatment (...) of this group of diseases. (shrink)

As Dobzhansky wrote, nothing in biology makes sense outside the context of the evolutionary theory, and this truth has not been sufficiently explored yet by medicine. We comment on Shanks and Pyles' recently published paper, Evolution and medicine: the long reach of "Dr. Darwin", and discuss some recent advancements in the application of evolutionary theory to carcinogenesis. However, we disagree with Shanks and Pyles about the usefulness of animal experiments in predicting human hazards. Based on the darwinian observation of inter-species (...) and inter-individual variation in all biological functions, Shanks and Pyles suggest that animal experiments cannot be used to identify hazards to human health. We claim that while the activity of enzymes may vary among individuals and among species, this does not indicate that critical events in disease processes occurring after exposure to hazardous agents differ qualitatively between animal models and humans. In addition, the goal is to avoid human disease whenever possible and with the means that are available at a given point in time. Epidemics of cancer could have been prevented if experimental data had been used to reduce human exposures or ban carcinogenic chemicals. We discuss examples. (shrink)

The unprecedented development of medical informatics is constantly transforming the concept of expertise in medical sciences in a way that has far-reaching consequences for both the theory of knowledge and the philosophy of informatics. Deep medicine is based on the assumption that medical diagnosis should take into account the wide array of possible health factors involved in the diagnostic process, such as not only genome analysis alone, but also the metabolome (analysis of all body metabolites important for e.g. drug-drug interactions), (...) microbiome (i.e. analysis of all bodily microorganisms interacting with host cells) or exposome (analysis of all environmental factors triggering potentially harmful cell mutations, such as UV radiation, heavy metals, various carcinogens, etc.). Deep data analysis is of tantamount importance for personalized diagnosis but, at the same time, hardly achievable by a regular human being. However, adequately designed artificial intelligence (e.g. a deep neural network) can undeniably be of great help for finding correlations between symptoms and underlying diseases. Nowadays AI applies to nearly every aspect of medicine, starting from the data analysis of scientific literature, through the diagnostic process, to the act of communication between physicians and their patients. Medical image processing algorithms greatly enhance the chances of successful recognition of melanoma or intestinal polyps. Communication tools designed for physicians use techniques known from social media to provide users with an opportunity to consult the case with colleagues from the same discipline. Natural language processing tools significantly improve doctor-patient communication by the automation of note-taking. Is this enough to support the claim that the non-epistemic competences in medicine are becoming more and more important? Can we attribute expertise only to a person? How is medical informatics changing the way most people usually understand human-computer interactions? (shrink)

Familial clustering of a disease is defined as the occurrence of the disease within some families in excess of what would be expected from the occurrence in the population. It has been demonstrated for several cancer types, ranging from rare cancers as the adenomatosis-coli-associated colon cancer or the Li-Fraumeni syndrome to more common cancers as breast cancer and colon cancer. Familial clustering, however, is merely an epidemiological pattern, and it does not tell whether genetic or environmental causes or both in (...) combination are responsible for the familial clustering. Familial clustering may be due to genetic predisposition to the disease, but exposure to environmental factors — shared by members of some families, but not by members of other families — may also cause familial clustering and hence mimic genetic inheritance in the study of nuclear families. Based on assumptions regarding the individual steps in the biological process starting with exposure to carcinogens and ending with death from disseminated cancer we suggest that genetic and environmental factors may both be involved in most of these steps. The present paper focuses on research methodologies necessary to discriminate between the effect of genes and family environment in the development of cancer. (shrink)

This paper, using modern Darwinian theory, proposes an explanation for the increasingly high incidence of breast cancer found among pre-and post-menopausal women living today in westernized countries. A number of factors have been said to be responsible: genetic inheritance (BRCA-1), diet (specifically the increased consumption of dietary fat), exposure to carcinogenic agents, lifetime menstrual activity, and reproductive factors. The primary aim of this paper is to demonstrate the value of a perspective based on Darwinian theory. In this paper, Darwinian theory (...) is used to explore the possibility that the increased incidence of breast cancer is due primarily to the failure to complete in a timely manner the reproductive developmental cycle, beginning at menarche and continuing through a series of pregnancies and lactation. On the basis of comparative data, we assume that most women in ancestral populations began having children before age 20 or so and tended to remain either pregnant or nursing for most of their adult lives. If a woman did not have a child by age 25 or so, she probably would never have one. Therefore, selection would probably not have acted against deleterious traits, such as cancer, that appeared after that age, just as it does not act against such traits in old age. (shrink)

This chapter contains sections titled: Moral Argument Science and Health Argument Social Policy Argument.

When new technologies create risks, government agencies use regulations to control the risks. This paper advances a method of evaluating a democracy’s regulation of risks. It assumes that a regulatory agency should act as the public would act in ideal conditions for negotiation if the public were rational and informed. The method relies on decision theory and game theory to ascertain whether a regulation has the public’s informed support. The Occupational Safety and Health Administration’s regulation of exposure to carcinogens (...) in the workplace illustrates the account of regulation. The illustration draws attention to a distinction between physical and information-sensitive risks. Regulations guided by the physical sciences alone may overlook the value of reducing information-sensitive risks. These risks exist objectively, and rational people generally have an aversion to them. An information-sensitive risk and an aversion to it may persist after acquisition of all available relevant information. Democratic regulation justifiably aims to reduce such risks. (shrink)

Oxycholesterols (OS) are formed from cholesterol or its immediate precursors by enzymatic or free radical action in vivo, or they may be derived from food. OS exhibit a wide spectrum of biological activities. In OS cytotoxicity, several mechanisms seem to be involved: e.g. inhibition of HMG‐CoA reductase activity, antiproliferative action, apoptosis induction, replacement of cholesterol by OS in membranes followed by changes in cellular membrane structure and functionality, and immune system functions alteration. Furthermore, OS may be mutagenic and carcinogenic and (...) may serve as intracellular signaling or regulatory molecules. Here we review OS cellular activities with special attention to the cytotoxic action in vivo and in vitro using experimental models. BioEssays 28: 387–398, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Genetic engineering is a rapidly evolving field of research with potentially powerful therapeutic applications. The technology CRISPR-Cas9 not only has improved the accuracy and overall feasbility of genome editing but also has increased access to users by lowering cost and increasing usability and speed. The potential benefits of genetic engineering may come with an increased risk of off-target events or carcinogenic growth. Germ-line cell therapy may also pose risks to potential progeny and thus have an additional burden of proof for (...) safety. Persons responsible for evaluating the ethics of genetic-engineering research programs or clinical trials should do so in light of the nature, integrity, and totality of the human person. Recent news of the implantation and birth of genetically engineered human embryos is just one example of increased rogue science. Health care institutions should consider what steps can be taken to prevent or slow this trend. (shrink)

„Substances capable of self-reproduction“ as cellular targets of chemical carcinogens.In the course of studies on chemical carcinogenesis, which included animal experiments with a carcinogenic azo dye and a mathematical analysis of the observed effects, Hermann Druckrey and Karl Küpfmüller showed in 1948 that carcinogens induce heritable changes by targeting cellular „substances capable of self-reproduction“. The authors did not discuss the chemical nature of these substances which remained unclear for a long time thereafter. It was not until 1964 that (...) deoxyribonucleic acid (DNA) was recognized, by Peter Brookes and Philip Lawley, as a target for the genotoxic action of chemical carcinogens. In retrospect, the results of Druckrey and Küpfmüller gave an early, indirect and until now not considered hint to an important role of DNA (the „substance“) malfunction in the development of cancer, since DNA is the only molecule capable of self-reproduction.The results are now appreciated in light of the scientific knowledge available at the time. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Surviving American Culture:On Chuck PalahniukEduardo MendietaIn an age in which American culture has become the United States' number one export, along with its weapons, low intensity conflict, carcinogenic cigarettes, its "freedom," and pornography, it is delightful and even a sign of hope that there are writers who have taken on the delicate and perilous task of offering a prognosis of what ails this culture. In the following essay I (...) argue that Chuck Palahniuk's works ought to be read as a mortician's report on American culture. Chuck Palahniuk broke into the literary world by way of the movie version of his first novel: Fight Club (1995). He has gone on to write six other novels: Survivor (1999), Invisible Monsters (2000), Choke (2001), Lullaby (2002), and Diary (2003). He also has published an interesting travel book, Fugitives and Refugees; A Walk in Portland, Oregon (2003), but since this is not properly fiction, I will not discuss it in this essay.1Clearly, Palahniuk has already produced a corpus worthy of careful consideration and analysis. Yet, as a west coast writer, far from the literary circles and brokers of the east coast, indeed far away from the clubs of self-promotion and self-monitoring that censure and hold in tight grip the monopoly of criticism that highlights "worthy literature," Palahniuk has not attracted a lot of critical attention. It is only with his most recent work Choke that he has began to be widely reviewed and commented on. In the following I provide a thematic reconstruction of each one of the six published novels, in chronological sequence. I will argue that Palahniuk is not trying to write the "great American novel," although he is profiling himself as a quintessential "American" writer in the midst of post–Cold War megalomania and celebrated Pax Americana. He has taken on a culture that has become so gargantuan, [End Page 394] fragmented, and differentiated but at the same time so rich, so self-reflexive, so historicized and also so mimicked that one novel cannot tell its story in one narrative with one dramatic thread. Many novels, many short cuts, many vignettes, are necessary: one polyphonic, asynchronous, temporally bi-directional, hyper-textual, and cyber-encyclopedic novel made up of individual novels, where each novel is the Bildungsroman of an American hero but told in reverse. These heroes, I will argue, are testimonies to the resilient power of individuals to resist even the most invasive and persistent onslaughts by culture on the physic life of freedom and individuality. I will also argue that he is neither a commercial nor academic writer; that is, he is not the kind of writer who writes either in order to maintain a living or secure tenure. He is a writer with a mission, a vision, and a very distinctive style. The stories that Palahniuk tells are stories that begin at the end, and end at the beginning: they are turned around Bildungsromans. They are, in other words, about unmaking, uncoupling, and disentangling our selves from the normal self into which we have been socialized. These stories are, thus, about the discovery of moral resources that lay dormant in the very simplicity of human solidarity and trust in our will to survive morally untainted, or at least redeemable. I will conclude by arguing that Palahniuk's novels are about surviving American Culture, and about how deviance is the health of the individual in a sick society.One could characterize Fight Club as the intelligent man's response to Robert Bly's Iron John (1990),2 or the fictionalized version of the Michael Kimmel's Manhood in America: A Cultural History (1996).3 Alternatively, one could argue that Fight Club is the fin-de-sieclé response to Barbara Ehrenreich's prognosis in her The Hearts of Men: American Dreams and the Flight from Commitment (1983) of 1970s and 1980s narcissistic and hedonistic masculinity.4 Chuck Palahniuk's first novel is a biting and poignant look at men in American culture after the end of affluence and the simultaneous "feminization" of masculinity. It is at the same time about the struggle for a viable sense of masculinity in an age in... (shrink)

ABSTRACT Persons injured as a result of exposure to toxic or carcinogenic substances are seldom able to recover damages from those who are responsible for the exposure. Tort law requires proof of causation, and causation is often unprovable because of long latency periods, because of the relative infrequency of the injuries and because many of the injuries among the exposed population are the result of other factors. A number of proposals for modifying the legal causation requirement to allow those who (...) create hazardous risks to be held liable for the injuries that materialise are considered and found inadequate. A proposal to treat risk exposure itself as an injury for which compensation under private law is possible is also considered and ultimately found incoherent. The paper concludes by arguing for a public law solution, modelled on criminal law, but providing compensation for victims. (shrink)

In After the Rights Revolution, Cass Sunstein confronts the ?Chicago? intellectual tradition on the effects of government regulation. While recognizing the many failures of regulation, Sunstein argues that most regulation serves a potentially useful purpose and that the courts can be relied on to correct the worst regulatory failures. He offers a dizzying array of prescriptions to ensure this outcome, many of which would appear to run afoul of clear congressional intent. In a more recent book, Breaking the Vicious Circle, (...) Stephen Breyer offers a different diagnosis. He sees health?safety?environmental regulation as essentially out of control because of the ?vicious circle? created by irrational and ineffective government responses to the public's concern about the risk of exposure to carcinogens. Breyer does not believe that this vicious circle of excessive and irrational regulation can be broken by the courts. Instead, he suggests the creation of an elite bureaucratic corps with the mission of proposing more effective and less costly approaches to controlling threats to human health. (shrink)

There are three main categories of rationale for withholding information or telling lies: if overwhelming harm can only be averted through deceit; complete triviality such that it is irrelevant whether the truth is told; a duty to protect the interests of others. Public health authorities are frequently having to form judgements about the public interest, whether to release information or issue warnings. In June 1992, routine surveillance detected patulin levels (a known carcinogen) in samples of apple juice exceeding safety threshold. (...) Remedial actions were promptly taken and it was planned to subsequently publish the information in the routine way. However, the media portrayed the handling of the problem as a conspiracy and there was a short term reduction in juice sales. In October 1995, the UK Committee on Safety of Medicines issued a warning about certain brands of the contraceptive pill, based on the interim results of three unpublished studies. The increased risk of thromboembolism was small, but the resulting scare led to an increase in unwanted pregnancies. The handling of the B.S.E. crisis in the U.K. also led to accusations of incompetence or conspiracy. Public health authorities have to handle uncertainty and frequently have to form judgements for public safety on the basis of evidence of poor quantity and quality. Their task is not helped by the sometimes conflicting agenda of scientists and media. The public also have differing perceptions and interpretations of risk. The series of scares and crises are having a detrimental effect on public confidence in public health authorities. (shrink)