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Waste and Pollution
Published in John C. Ayers, Sustainability, 2017
For a given compound the EPA sets the maximum contaminant level at or below the threshold dose, although in reality dose–response curves have not been derived for most chemicals. To complicate matters further, dose–response curves are usually not linear (Figure 14.3). However, as a rule of thumb, “dose makes the poison,” that is, almost any chemical can become toxic if a person is exposed to very high levels. The higher the dose, the more probable there will be a negative health effect. Conversely, the probability that an environmental carcinogen caused an individual’s cancer increases with the dose. Sometimes high doses can result from natural causes. For example, people may be poisoned by drinking well water with unsafe levels of heavy metals that were leached from the aquifer, or mineral dusts can contain asbestos minerals that cause lung cancer. More commonly high doses result from anthropogenic contamination.
Containment Technology
Published in Terry Jacobs, Andrew A. Signore, Good Design Practices for GMP Pharmaceutical Facilities, 2016
“The dose makes the poison” was first expressed by Paracelsus (Philippus Aureolus Theophrastus Bombastus von Hohenheim, 1493–1541), who intended the comment to communicate a basic principle of toxicology, which is that a substance can produce harmful effects associated with its toxic properties only if it reaches a susceptible biological system within the body in a high enough concentration. The basic principle of pharmaceuticals is to create a positive, not negative, effect on the patient. To accomplish the positive effect, the correct dosage for the intended patient is carefully designed and tested by the pharmaceutical manufacturing company. Extensive testing is conducted also to determine what quantity of the drug will create a negative effect. The negative effect can come in several different ways: a person can consume a higher than intended dose, or personnel working with and around the drug can be exposed to a level that will create a negative effect. The entire life cycle of the drug, from discovery to administration to the patient, is associated with exposure risks.
Is there a safe or risk-free level of asbestos exposure?
Published in Dorsett D. Smith, The Health Effects of Asbestos, 2015
The basic principle of toxicology, elucidated in the 1547 manuscript by Paracelsus, is “What is that is not a poison? All things are poison and nothing is without poison. It is the dose only that makes a thing not a poison.” (Ottoboni, MA. The Dose Makes the Poison—A Plain Language Guide to Toxicology, 2nd Edition. New York: Van Nostrand Reinhold, 1991.) Toxicology focuses on the adverse effects of potential toxic substances, with the focus being determining adverse effects. Everything is potentially toxic, including the air we breathe and the water we drink. Excessive inhalation of oxygen will cause oxygen toxicity, and excessive ingestion of water causes water intoxication, which can be lethal. Excessive exposure to various asbestos fibers may be injurious and cause asbestos-related disease. The basic question is how much asbestos exposure is dangerous, or what level of exposure, based on fiber size and fiber type, is necessary to cause an adverse effect? The answer to that question has been referred to governmental agencies such as the ACGIH, NIOSH, and EPA to answer. Over time, new information has been published in the scientific literature concerning the safe dose of asbestos exposure, beginning in 1971, when the federal government assumed the rule-making from the states. Over 23 years, the OSHA has gradually lowered the permissible exposure limit from 12 fibers/cc in 1971 to 0.1 fibers/cc in 1994, where it remains today (see Figure 22.4). (Martonik JF, Nash E, Grossman E. The history of OSHA’s asbestos rulemakings and some distinctive approaches that they introduced for regulating occupational exposure to toxic substances. AIHAJ 2001;62:208–17.)
Xenobiotic metabolism and transport in Caenorhabditis elegans
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
Explicit discussion of the strengths and limitations of C. elegans as a model for toxicological research may be found in several review papers and books (Hunt 2017; Maurer, Luz, and Meyer 2018; Queiros et al. 2019; Wang 2019a, 2019b, 2020; Weinhouse et al. 2018), and thus will not be repeated here. The focus of this review will be on one very important and oft-cited limitation: the absence of detailed understanding of xenobiotic transport and metabolism processes that regulate concentrations of chemicals and metabolites that reach molecular targets. The study of these processes is fundamental to toxicology, pharmacology, and drug discovery. A truism in toxicology is that “the dose makes the poison,” and it is not possible to truly understand the toxicity of a chemical without understanding how much of it (or its metabolites) has reached specific molecular sites of action. Similarly, it is not possible to extrapolate effects observed in one species (e.g., worms) to another (e.g., humans) without being able to compare internal toxicant concentrations. In toxicology, a distinction is made between toxico(pharmaco)kinetics (understanding the absorption, distribution, metabolism, and excretion (ADME) processes that regulate xenobiotic transport and transformation processes) and toxico(pharmaco)dynamics (understanding the interactions of xenobiotics with molecular targets including receptors, DNA, and proteins).
Where there’s smoke, there’s fire: focal points for risk communication
Published in International Journal of Environmental Health Research, 2018
Frans E. Greven, Liesbeth Claassen, Fred Woudenberg, Frans Duijm, Danielle Timmermans
The basic principle of toxicology that ‘the dose makes the poison’ means that any substance (even water) can cause a toxic effect if the dose is great enough(Klaassen 2008). Because of the relatively low concentrations of hazardous materials at a great distance of a fire, most experts consider the health impact of a chemical fire as very limited(Upshur et al. 2001; Greven et al. 2009). While most lay participants knew that the concentration of hazardous materials in the smoke quickly dissipates with distance, a larger majority did not seem to fully understand the dose–response relationships. They focus on the alleged hazardous (i.e. carcinogenic) quality of involved substances and do not correctly adjust for the dissipation of the concentration with distance.
No clear concerns related to health risks in the European population with low inorganic arsenic exposure (overview)
Published in Human and Ecological Risk Assessment: An International Journal, 2023
Zdenka Šlejkovec, Tine Bizjak, Milena Horvat, Ingrid Falnoga
The dose makes the poison is a fundamental concept of toxicology (Klaassen 2013). The toxicity of arsenic at high doses is not a subject of debate although its potential impacts on human health at environmental and dietary exposure to low amounts are not as clear as its toxicity at high concentrations. The binding of trivalent iAs and trivalent organoarsenic compounds to sulfhydryl groups of several peptides and proteins can on one side immobilize arsenic but might at the same time, if levels are high enough, directly or indirectly damage critical proteins and enzymes resulting in cytotoxicity and regenerative hyperplasia (Cohen et al. 2013) and eventually lead to disease, including cancer. There are also experimental data pointing to adaptive, even beneficial responses at low levels. The assumption that direct extrapolation from high concentrations could predict health effects at very low concentrations (linear approach) is ignoring such low-dose effect observations for many stressors, despite using the same cancer slopes for low and high exposure levels could potentially bias in the direction of low-dose linearity. The linear approach was for arsenic repeatedly used and also repeatedly seriously questioned in the past and more recently by several authors (i.e., Cohen et al. 2019, 2021; Tsuji et al. 2019, 2021) who are presenting the evidence for the existence of a threshold and nonlinearity. The shape of the low-dose As-response curve at concentrations approaching zero (J-shape, U-shape, threshold) is still under investigation. The evidence for nonlinearity and potential methodological pitfalls in recent dose-response evaluating epidemiology seems to have been clear enough to trigger the ongoing reassessment of iAs risks and risk methodology by EPA (US EPA 2019). However, (as discussed above) EPA is still not relying on the mode of action but tries to solve the problem on a mathematical basis using various sophisticated models and low-exposure epidemiological data without including the mode of action which could justify their relevance to human hazards, and risks. Their recently published modeling of bladder cancer epidemiological studies (Allen et al. 2020) is based on a model not sensitive to nonlinearity at lower doses, as shown by Shao et al. 2021. Next to iAs, the no-threshold approach is currently revised for low-dose radiation-induced health risks and some other DNA-reactive and epigenetic experimental carcinogens (Kobets and Williams 2019; Tharmalingam et al. 2019). Ted Simon in his recent book (Simon 2019) claims that “… the linear no-threshold hypothesis for chemical carcinogens was derived from early 20th-century work on radiation mutagenesis and has been used for the past 25 years. However, recent investigations of radiation mutagenesis and the increasing knowledge about fundamental biology and nature of cancer suggest that this hypothesis is based on flawed assumptions and is inconsistent with the biology.”