Discussions: Question set 1. Question 6. Chronic Toxicity & Carcinogenicity

Topic: Question set 1. Question 6. Chronic Toxicity & Carcinogenicity

Subject: Question set 1. Question 6. Chronic Toxicity & Carcinogenicity Posted: Mar-04-02 at 3:59 PM by Kenneth Campbell

6. Note the emphasis of chronic toxicity testing and mutagenesis testing on carcinogenesis. Is this emphasis currently appropriate, or are there other possible chronic outcomes to be concerned with?

Posted: Feb-12-03 at 10:27 PM by Ivana Djuretic

Certainly, as scientific methods and techniques get more advanced it will become much easier and cost-effective to assess various other effects of toxicants beside carcinogenesis. Why is this important? For instance, a particular signaling protein affected by a toxicant can cause an increase in cellular proliferation (then cancer) but this protein might also have other functions either in the same organ or in different organs. Toxicant might also affect more than one protein with similar binding clefts (e.g. ATP is a substrate for various enzymes). Activation of one tyrosine kinase receptor by a toxicant can have multiple effects via diverging signaling cascades. Genes with distinct functions could be affected by mutagenesis (see chapter 3 for many specific examples).Continuous displacement of homeostasis can therefore lead to various other outcomes that might not be readily observed under submaximal doses but require further investigation (as mentioned in Session 2 notes: "neural degeneration, arthritic conditions, vascular rigidity, loss of muscle mass, loss of bone mass, decline in immune function"). Animals that undergo toxicity testing for carcinogenesis should be used for further microscopic and biochemical examination. Are there any increases/decreases in protein expression in experimental group compared to controls, any changes in tissue/organ architecture? Do animals show any of the effects mentioned above? Recent advances in proteomics such as DNA, mRNA, and protein chips will allow faster analysis.

Posted: Feb-13-03 at 5:52 PM by Erin Valentine

Although it remains important that the emphasis of chronic toxicology testing is on carcinogenesis and mutagenesis, other possible outcomes are similarly significant. One such example is chronic exposure to mycotoxins. Mycotoxins are secondary products of Fungi found primarily in food or animal feed due mainly to poor storage environments. Due to their lipophilic nature, these toxins are generally stored in fat cells. The various species produce a variety of mycotoxins of which a few have been studied extensively for toxicity in wide ranges of animal species (mainly farm and laboratory animals). Symptoms exhibited by mice and rats chronically exposed to mycotoxins included, along with carcinogenesis, such deleterious effects as extensive liver damage, gastric ulcers, and thymic depression. It has been shown that the mycotoxin, aflatoxin, is cytotoxic due to its ability to induce lipid peroxidation leading to oxidative damage in certain cell types. Other mycotoxins damage cells through action on cellular respiration indicated competitive inhibition of ATPase succinate dehydrogenase, and cytochrome C oxidase. Some examples inhibit protein and DNA synthesis, compromise immunity, and/or disrupt the endocrine system (above issues reviewed in Hussein and Brasel 2001) These effects could damage any number of essential functions for survival. The reason that it is important to seriously consider these effects alongside carcinogeneisis and mutagenesis is that they may be just as deadly. In the case of mycotoxins, chronic exposure to humans may come in the form of consuming milk or meat from intoxicated farm animals, consuming contaminated food directly, and inhaling air from contaminated buildings. Lately, the issue of infected buildings has repeatedly been in the news, and the report often includes contamination of a school with mold and many sick children.

Hussein, HS and Brasel JM, Toxicity, metabolism, and impact of mycotoxins on humans

and animals. Toxicology. 167 (2001) 101–134.

Posted: Feb-13-03 at 10:36 PM by Lisa McIntosh

Carcinogenesis is certainly emphasized as a selective endpoint for toxicity testing, although noncarcinogenic effects that may potentially impact one's life are by no means considered a weaker endpoint. Not all substances are carcinogenic; therefore, long-term, low-dose exposures to such substances obviously should be evaluated with regard to noncarcinogenic, nonlethal effects. (Furthermore, some substances shown to be carcinogenic in laboratory animals have not been proven to cause cancer in humans).

Posted: Feb-15-03 at 11:14 AM by Hanae Hiyoshi

Chronic toxicity test usually requires at least 1,000 animals and 18 months to complete. It should have the same route of exposure that would occur in humans and needs a close watch every day. I think the current emphasis of chronic toxicity testing is pretty appropriate to check on carcinogenesis, but the test is expensive and there is no standard measure for chronic toxicity, unlike LD50 for acute toxicity. Humans are generally more vulnerable than the tested animals, and different species have different way of responding to toxic substances. Today the estimation of human risk is still one of the difficult problems, since quantitative risk analysis is especially difficult to make relationships based on animal data, while qualitative risk analysis is relatively easier to develop by finding some negative toxic effects in the tested animals although the applicable toxicity use level is quite different in each country.

Posted: Feb-16-03 at 10:09 PM by Michael George

Chronic testing looks at periods from 6 months – two years. These tests look at exposure over most of the animal's lifetime. These tests require a minimum of 1000 animals. These animals have to free of any tumors. These studies look at MYD (maximum tolerable dose). These tests are fairly appropriate but can be costly and errors do occur. Humans have different responses than lab animals and generally are more vulnerable. Estimating responses to toxicants in humans is still difficult today since what might be toxic in lab animals isn't necessarily going to be toxic in humans and vice versa.

Posted: Feb-18-03 at 12:30 PM by DINA KATZ

Since cancer, speaking extremely generally, is caused by (1) a mutation of some sort in DNA which then causes (2) uncontrolable mitotic division of the originally affected cell or tissue, with the potential to (3) metastacise, there are several routes in which a toxin can either induce or enhance cancerous development. General toxicity testing is. of course, appropriate, just to see if any physiological response is elicited, and mutagenesis testing checks for the first part of my definition. However, a mutation may or may not lead to cancer, and it is, in my opinion, more important to check for the ability of a toxin or toxicant to break the normal regulation of a cell cycle. The toxin/toxicant may not be mutagenic itself, but may cause the disruption of the cell cycle, possibly in addition to damage done by some other agent previously, which damaged it and yet did not cause the cancer cascade. There is also the possibility of a toxin/toxicant damaging cell-to-cell connections and initiating metastasis of the cancerous cells.

Old

Allison:

February 20, 2002

6. Chronic toxicity tests are performed to assess the cumulative toxicity of chemicals, which often include a consideration of the carcinogenic potential of chemicals so that a separate study that soley addresses carcinogenity does not have to be performed. Chronic toxicity assays are regulated with guidelines that require that both benign and malignant tumors be in the evaluation. While this type of testing may be validated with discoveries of potential cancer causing agents, there are some problems. All known chemical carcinogens in humans have been found to be carcinogenic in some species but not in all laboratory animals. However, all chemicals that are

carcinogenic in animals are carcinogenic in humans. Species variation and genetic variation within a species being tested may account for some discripencies when chronic testing for carcinogens is applied. Information about the mechanism of action of the carcinogen may indicate that a positive response in animals is not relevant to humans and may be irrelevant for

human risk assessment. In this case, many question the purpose of chronically testing animals that may not provide results that actually relate to humans.

Another issue with chronic toxicity testing is that they are used mainly for carcinogenic studies when the possibility of other toxic effects and disease may occur. These other effects include, neurodegenerative disorders, problems with other organs, and toxic effects to the digestive and

reproductive systems. Also, many chronic studies expose agents in one or two forms of delivery but do not test the effects of exposing the toxin through another method of administration. This may also provide results that differ from carcinogenic effects but instead lead to various other diseases and malfunctions.

Joanne:

February 20, 2002

6) The emphasis on chronic toxicity with respect to carcinogenesis is presumably due to the many oncogenic promoting agents in the environment as well as the relatively easiness in measuring them. As our society becomes more sophisticated in terms of understanding,

technology and preventative strategies, it is certain that the range of chronic toxicity testing will

expand.

Neetu:

February 20, 2002

6. Chronic toxicity is performed to find out the possible toxic effect s of a certain chemical. It is

also done to check if the drug has any carciogenic potentials. The exposure time is long (more

than 3 months) for chronic toxicity; excatly how long depends on how long the drug will be used

for in humans. High dose is required for mutagenesis testing and chronic testing requires the

use of a drug for a long period of time. These two factors (high dose and long time exposure) can

be deleterious for the subjects. Therefore, in order to perform chronic toxicity, it is very important to keep maximal tolerance dose (MTD) concept in mind. MTD is a maximum dose that can be used in testing subjects without harming them before they go through the rest successfully. Also, it is important to use heatanimals ; animals whose medical history has been clear of any tumors.