Topic: Question Set 1. Question 1. Questions arising from the historical background of toxicology.

Subject: Question Set 1. Question 1. Questions arising from the historical background of toxicology. Posted: Mar-04-02 at 4:05 PM by Kenneth Campbell

1. The idea of causality arose during the middle ages and Renaissance. This builds on careful observation and testing. How might this give rise to the notions of occupational hazards or the nonmystical explanation for oncogenesis?

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Posted: Feb-12-03 at 11:59 AM by Erin Valentine

1. The idea of studying causality through careful observation and testing might give rise to the notion of occupational hazards because certain occupations expose workers to unique risks of exposure. If particular subsets of workers are all experiencing a similar disease or condition, the logical way to explain the symptoms is to carefully observe the working conditions. This would entail sampling the environment in search of the causative agent, or the "toxicon". Potential candidates could then be used in animal or in vitro tests to determine response to various dose levels, site of action and what types of symptoms are observed in the test subjects. They could also undergo biochemical analysis to determine structure/activity relationships. The information gathered could then be used to determine the causative agent and could also be used to infer other potential hazards. This type of testing could then also be used to test other potentially hazardous working environments before workers exhibit symptoms. This would allow for preventative measures to be taken against toxic exposure.

In the case of non-mystical explanation of oncogenesis, the same process applies. In the onset of unexplained cancer, one can carefully observe the afflicted individual's potential exposure to a potential carcinogen. Similar tests to those described above could then be performed to identify the culprit.

Posted: Feb-12-03 at 3:38 PM by Lisa McIntosh

The process of simple observation from occupational or incidental exposures may be suitable for noncarcinogenic effects resulting from acute exposures; however, for chronic adverse effects or carcinogenesis, it is not as easy a matter as to pinpoint the potential culprit. Liver cancer, or heart disease, for example, may result from a lifetime of cumulative effects of numerous causative agents, which may or may not be obvious based on the individual's exposure.

Posted: Feb-13-03 at 10:34 PM by Lisa McIntosh

"Watch and learn" tactics. In the past, people have noted adverse effects associated with exposure to particular substances. Likewise, it was noted that certain occupations had correspondingly higher incidences of diseases (e.g., "Mad Hatters" syndrome, resulting from mercury toxicity (neurotoxicity). Mercury was commonly used by hat makers…..). As for oncogenesis, the same premise holds: exposure to a particular substance eventually initiated the onset of cancer (e.g., the elevated incidence of lung cancer among smokers). One problem with this approach, however, is that a particular type of cancer (or, say, a nonspecific noncancer effect) may correlate with a substance's use, but may not necessarily be directly related to exposure. Simple observation does not take into account confounding factors such as the incidence of background cancer rates, or the numerous other entities in our lives that may also attribute to adverse effects (e.g., diet, acute exposures, etc.)

Posted: Feb-15-03 at 11:30 AM by DINA KATZ

During the Renaissance, the idea of scientific experiments and replicability arose. It became understood that an event can be caused by something non-immediate. The spread of literacy and printed works made it easier for scientists and others to share observations and note patterns, such as the high occurrence of scrotal cancer in chimney sweepers. Likewise it was known that mining and covering building domes with gold leaf (I believe the gold was in a mercury solution) were dangerous occupations, because many of these profesionals died relatively quickly of similar diseases, such as lung problems. While the exact mechanisms of lung injury were not known, the cause-effect relationship was established. Similarly, while initially oncogenesis was attributed to mystical causes, the observation of patterns of lifestyle and environment among victims contributed to the uncovering of certain cause-effect relationships, like the above-mentioned scrotal cancer of chimney sweepers and, more recently, lung cancer and emphysema among heavy smokers.

Posted: Feb-15-03 at 2:59 PM by ERIC FAULKNER

While scientific advancements of the cause and effect relationship of toxicants on the human system did occurred during the Middle Ages, one could say that these were great scientific alchemy experiments than the precusors of government regulatory bodies like OSHA, EPA, and the NIH. One pioneer of the Middle Ages, Catherine de Medici, tested toxic concoctions on men. Now, her horrific crimes can be interpreted to modern toxicology terms such as onset of action, specificity of action, and clinical significant. The fate for her evil ways was execution, but one could argue that her scientific studies are exactly what occurs during Phase I, II, and III clinical trials of new chemical entities therapies. Overall humans have tried to learn from there mistakes and this what has initated governmetal control Back in the 1900's one pharmaceutical company killed 108 children with their cough drop medicine. They had used ethylene gylcol instead of proylene glycol in their formulation. Their medicine was termed the Elixr of death and hence the FDA was then established soon afterwards.

With regards to the explanation oncgoneiss, the formation of tumors can be enviromentally stimualed as well as genetic inherited. Indeed OSHA is there to protect workers from safety and toxic hazards, but if they were really that concerned why does mining still exist. An occupation were many maligancies have been well document. Maybe humans have not really progessed as much as we have thought. And as far as governmental control, the pharmaceutical company that made the Elixir of death is still in business.

Posted: Feb-15-03 at 4:19 PM by ERIC FAULKNER

(Note: The spell check was not saved from the original response)

While scientific advancements of the cause and effect relationship of toxicants on the human system did occurred during the Middle Ages, one could say that these were great scientific alchemy experiments than the precursors of government regulatory bodies like OSHA, EPA, and the NIH. One pioneer of the Middle Ages, Catherine de Medici, tested toxic concoctions on men. Now, her horrific crimes can be interpreted to modern toxicology terms such as onset of action, specificity of action, and clinical significant. The fate for her evil ways was execution, but one could argue that her scientific studies are exactly what occurs during Phase I, II, and III clinical trials of new chemical entities therapies. Overall humans have tried to learn from there mistakes and this what has initiated governmental control Back in the 1900's one pharmaceutical company killed 108 children with their cough drop medicine. They had used ethylene glycol instead of propylene glycol in their formulation. Their medicine was termed the Elixir of death and hence the FDA was then established soon afterwards.

With regards to the explanation oncogenesis, the formation of tumors can be environmentally stimulated as well as genetic inherited. Indeed OSHA is there to protect workers from safety and toxic hazards, but if they were really that concerned why does mining still exist. An occupation were many malignancies have been well document. Maybe humans have not really progressed as much as we have thought. And as far as governmental control, the pharmaceutical company that made the Elixir of death is still in business.

Posted: Feb-15-03 at 4:38 PM by Michael George

During the Middle Ages and the Renaissance, the beginnings of careful observations and testing began. Looking at the cause and affects of a toxicant/toxin began. For example, Catherine de Medici looked at toxic effects on the poor by noting the rapidity of the toxic response (onset of action), the effectiveness of the compound (potency), the degree of response of the parts of the body (specificity, site of action) and the complaints of the victims (clinical signs and symptoms). As cruel as these experiments were, they were really an early version of the Phase I, II, and III testing. During the Renaissance, Parcellis was the first to look at a toxicant as a chemical entity rather than a mixture of some sort. His 3 concepts were:

1.) Experimentation is Essential in examination of responses to chemicals.

2.) One needs to make a distinction between therapeutic and toxic properties of chemicals.

3.) These properties above are sometimes distinguishable by dose but not always.

4.) One can ascertain a degree of specificity of chemicals and their therapeutic or toxic side affects.

This can really be seen as the beginning of the dose-response relationship. Percellis also looked at the etiology of diseases associated with miners and how to treat/prevent them. Also the hazards of metal working began with the works of Ellenborg warning of toxicity of mercury and lead in goldsmith work. All these lead to looking at the occupational hazards of toxicants and looking at nonmystical explanations for oncogenesis.

Posted: Feb-16-03 at 8:18 PM by Shaun McAuliffe

If one considers simple hunter-gathering an occupation, causality via observation and testing likely developed prior to the middle ages and Renaissance, during early hunting and foraging expeditions. Early man likely encountered poisonous plant, animal and insect species. Tribal leaders likely recorded the species of plant, animal and insect that caused a toxic response in a member; thus establishing early causality. Over time I imagine that unexplained and/or mysterious death previously attributed to mystical causes was later attributed to an exposure to a naturally occuring toxin/species delivering said toxin. Once studied and understood, it is evident from early manuscripts that early man was able to apply this toxicological knowledge to hunting and warfare.

This early study was later refined by persons like Maimonides and Hippocrates who furthered the study of toxins and early toxicants. They and their peers authored papers on poisoning and antidotes. Their work helped to define how most poisons/toxins of the time manifested themselves and establish the notion of bioavailability.

As this study was furthered, individuals like Paracelsus and Ramazzini documented disease trends amongst asbestos workers, miners (radon, dusts), metallurgists, printers, potters, weavers and end users of products and/or resources. Like the early hunter-gatherers and their peers furthering the study of poisons and antidotes, I image that individuals like Ellenbog, Paracelsus, and Ramazzini desired to further establish the causal relationships between occupation and disease. Once established and like Maimonides and Hippocrates, Ellenbog, Paracelsus, and Ramazzini worked to develop treatment and prevention strategies.

Scientists like Percival Pott were able to build upon the foundation that Paracelsus and Ramazzini had established. Armed with a broader depth and understanding of biological and chemical science, scientists like Pott were able to establish that specific occupational exposures led to the development of organ and/or tissue specific disease and/or manifestations.

In summary, it is clear that man's pursuit to understand causality has led to our present understanding of occupational disease and oncogenesis. Perhaps as we further broaden our base of knowledge, man will not only be able to prevent the incidence of occupational disease but also repair the damage that an accidental exposure has caused.

Posted: Feb-18-03 at 3:15 PM by Diana Esshaki

The idea of causality seems to have developed around the introduction of the physician-alchemist, Paracelsus. He promoted the idea of a dose-response relationship. Looking at the relation of cause (i.e. "toxicon" exposure) and effect (i.e. disease, death) parallels Paracelsus' studies of how chemical entities can elicit various responses in individuals- both neg. and positive.

The idea/doctrine that "all things" have a cause definitely give rise to the notions of occupational hazards and nonmystical explanations for oncogenesis. For example, exposure to mercury and lead (cause; high dose)leads to disease (effect; response). Also, in the field of oncology, the role of soot in scrotal cancer demonstrated that the cause of disease was nonmystical (moving away from antiquity beliefs). As the book noted (the big picture), the idea of causality has improved medical practices, given a greater understanding to the broader fields of biology and chemistry, developed the beginnings of the scientific method (Campbell), and aided in prevention as well.

Posted: Feb-18-03 at 10:25 PM by Ivana Djuretic

I would just point out again the Age of Enlightment and the Industrial Revolution as major breakpoints in human history as far as toxicology is concerned. Throughout most of the history, including the Middle Ages, concern about the toxic effects of chemicals has been focused on poisons which act quickly and result in death. Socrates ingested hemlock to commit sucide. Infamous Toffana made many young married women wealthy widows by her arsenic containg cosmetics. Since exposure to these chemicals was not common and the risks were well known there was little public concern about these poisons.

Gradually we became more concerned with poisons, especially those that cause adverse effects after long periods of exposure. Industrial revolution has led to new and increased uses of known chemicals and the synthesis and widespread use of newly developed chemicals which has started a greater awareness of possible adverse health effects of chemicals other than lethality. More recently, increase in the average human life span due to cures and treatments for infectious diseases has made chronic non-infectious diseases more common and opened up a whole new area of research for toxicology.

Posted: Feb-20-03 at 0:17 AM by Ivana Djuretic

Referenced from:

www.iet.msu.edu/tox_for_public/riskasmt.htm

Old

Joanne:

February 19, 2002

1) The idea of casuality would potentially give rise to the notions of occupational hazards and/or the nonmystical explanations for oncogenesis by one's observing and posing a plausible causal relationship between the environment (work or otherwise) and an adverse (cancer promoting ..etc) reaction in the exposed individual. Instead of attributing ailments to superstitious beliefs, they had begun to establish the fundamental beginnings of the scientific method.

Allison:

February 19,2002

1. Occupational hazards associated with metal working were recognized during the 15th century. Paracelsus published a major piece of work addressing the etiology of miner's disease, along with treatment and prevention strategies.

Occupational diseases and causuality increased during the Industrial Revolution. The recognition of the basis behind scrotal cancer among chimney sweeps was the first reported example of polyaromatic hydrocarbon carcinogenity. These findings led to improved medical practices and prevention. Through careful observation, diseases that were prevelant among

a certain group of workers or people led to testing and experimenting on metals, plants, and minerals that they might be exposed to or using in their daily activity. This led to the understanding and further development of determination of how workers were becoming ill and the specific cause of these diseases.

Neetu:

February 19,2002

1. The occupational hazards and causalities were very commonly occuring in olden days.

People were perhaps, exposed to many chemicals and other hazardous material in their work

environment due to ignorance or they simply did not have any other choice. They had to work in

the environment they were working in bceause there were not many jobs and because they had

to provoide living for themselves and their families. After the industrial revolution, people started	becoming educated and taking more precautions, which made the working environments safer. With the advanced type of technology, and medical techniques, conditions are much better now than they were during industrial revolution. Learning, understanding and taking precautions while working, definately helped prevent occupational hazards.

Discussions: Question set 1. Question 2. Questions arising out of the historical background of toxicology.

Topic: Question set 1. Question 2. Questions arising out of the historical background of toxicology.

Subject: Question set 1. Question 2. Questions arising out of the historical background of toxicology. Posted: Mar-04-02 at 3:43 PM by Kenneth Campbell

2. What information already discussed is subsummed in the notion of biochemical kinetics?

Posted: Feb-12-03 at 12:55 PM by Erin Valentine

1. The similarities between enzyme kinetics and toxic effects are apparent when comparing dose-response curves to the plot of the Michalis-Menton equation also called the rate equation. The concentration of substrate on the X-axis is analogous to the dose and the velocity of the enzymatic reaction on the Y-axis is analogous to the response (efficacy). The median lethal dose (LD50) is analogous to the Km., the substrate concentration at which the reaction velocity is half-maximal, ½ Vmax. A small Km means that the enzyme achieves maximal catalytic efficiency at low substrate concentration. A small LD50 means that 50% lethality is reached at a low dosage of the toxicant. This also applies to the effective dose (ED) and toxic dose (TD). The mechanisms that facilitate the toxicants delivery to its target site could potentially influence the LD50 or ED50. If the facilitators decrease the dosage needed to reach the half-mark, they would be akin to catalysts of an enzymatic reaction.

Posted: Feb-13-03 at 0:50 AM by Ivana Djuretic

Toxicants affect their targets (enzymes) by binding to them in the same ways their normal substrates do: noncovalently and covalently. Examples: TCDD binding to aryl hydrocarbon receptor, and acridine yellow to DNA in a noncovalent manner; metal ions and free radicals are able to form covalent bonds with biomolecules.

Just like their normal substrates, toxicants can stimulate their target molecules and hence cause their dysfunction by activating or inhibiting them at inappropriate times. Well known are microtubule and actin impairing drugs such as colchicin and phalloidin or morphine which activates opiate receptors.

Toxicants can also destroy their targets upon the chemical attack by means of cross linking and fragmentation. Some chemicals are just big enough to bind to the cell surface proteins inducing antibody production and evoking an immune response (e.g. drug induced lupus, agranulocytosis, and hepatitis like syndrome).

Posted: Feb-13-03 at 10:32 PM by Lisa McIntosh

Chemical absorption, transformation, elimination, etc. is variable not only among substances, but among individual receptors (as in a human receptor) as well as on a cellular or subcellular level. In other words, toxicity is a function of chemical application, uptake, and transfer to a target, each of which in turn are dependent on the organism's distinct physiology and biochemistry.

Posted: Feb-15-03 at 11:45 AM by DINA KATZ

The dose-response curves of toxic substances on living organisms are similar in shape to virtually any plot of some effect of a chemical (in varying amounts) on a living organism, such as an enzyme and its product's concentration or even ingestion of glucose and and its level in the bloodstream. This is because the general mechanisms of any substance's function are similar: There is a minimal dosage at which an effect is found, when the substance's amount is sufficient to trigger a reaction, a subsequent somewhat linear relationship between dose and effect (though the slope will differ), and a later reduction in the rate of effect increase. This last may be due, depending on the type of effect observed, to a saturation of receptors for the chemical, or possibly to the death of the organism and shutdown of biological processes in the case of a highly toxic substance.

Posted: Feb-15-03 at 4:51 PM by ERIC FAULKNER

Biochemical kinetics refers to the rate at which a reaction takes place (Purich and Allsion). In mammalian systems, kinetic mechanisms play a vital function in metabolic pathways, the mechanistic action of enzymes, and the processing of genetic material. The biochemical kinetics covered in class was focused on a sigmoidal curve. While simple in structure, this shape pertains to a wide variety of biological and chemical systems; titration curves, isoelectric points of proteins, and curves exhibited by regulatory enzymes. This sigmoidal shape also exists in toxicology and is seen with the quantal-dose response relationship curve. The quantal dose response is used extensively in toxicology. First, the LD50 is determined where 50% of animals tested die from a certain dose. Second, a range of doses are used in a larger number of animals. From this a sigmoidal curve can be obtained. As with all biochemical kinetics, a saturation point exists where a stimulus will no longer result in an effect. For enzyme kinetics, only so many active sites exist on the enzyme for the substrate to bind. For a cumulative mortality curve, only so much dose can be given before death occurs.

that regulate These enzymes are called regulatory enzymes, the precursor or starting point at the metabolic process

Posted: Feb-17-03 at 0:31 AM by Shaun McAuliffe

Our discussion of biochemical kinetics touched upon the following:

1. the rate and/or response to a given toxin and/or toxicant could be graphically depicted as a dose-response curve;

2. the dose-response curve is most often sigmoidal;

3. curves may be individual or quantal;

4. the basal, middle and maximal points of the curve may correspond to a wide variety of endpoints;

5. cellular, tissue, organ, individual and population variability may be attributed to dosage, duration and frequency of dosage, route of exposure, chemical and/or physical interaction, genetics, environment and a wide variety of other factors

6. a greater level of confidence exists around the linear portion of the curve;

7. the lack of confidence at the asymptotic portions of the curve is due to factors including hypersusceptibility, the inability to define sub-threshold responces, and resistance.

Old

Subject: Re:Question set 1. Questions arising out of the historical background of toxicology. Posted: Mar-04-02 at 5:51 PM by Kenneth Campbell View the history for this message Reply Edit the message Re:Question set 1. Questions arising out of the historical background of toxicology. Delete the message Re:Question set 1. Questions arising out of the historical background of toxicology.

Joanne:

February 19,2002

2) The notion of biochemcial kinetics was encompassed

in our discussion of dose-response relationships as

well as routes of entry of toxins/toxicants. For

instance genetic backgrounds of the specimen in

question ( recipient of toxin/toxicant) will have an

effect on the biochemical result depending on its

underlying genetic makeup. Such variations include:

susceptibility to toxins/toxicants as well as the

ability to excrete/eliminate toxins/toxicants once

they infiltrate through the biological system. The

particular route of entry may be more significant

dependent upon the genetic background of the

individual organism.

Subject: Re:Question set 1. Questions arising out of the historical background of toxicology. Posted: Mar-04-02 at 5:58 PM by Kenneth Campbell View the history for this message Reply Edit the message Re:Question set 1. Questions arising out of the historical background of toxicology. Delete the message Re:Question set 1. Questions arising out of the historical background of toxicology.

Allison:

February 19,2002

2. Dosage and form of delivery and the aspect of bioavailability are

parts

of biochemical kinetics. Many toxicant problems occur when naturally

occuring toxicants are concentrated and exposed to other people.

Exposure

at low levels over a long enough time for the toxicants to be

deactivated

either by metabolism or adsorption to surgaces reduces the risk of a

toxic

response. However, if the same total dose is provided over a shorter

period

of time, the toxic response will be more observable due to the

inactivation

and reduction of metabolic and adsorption capacities. The forms of

delivery

are also important factors in biochemical kinetics. Lipophilic

materials

will not be adsorbed on hydrophobic surfaces like charcoal or clay

and the

toxicant will be unavailable to biological systems, unless extreme pH

or

mechanical agitations allow the toxicant to pass through the

digestive

system. Dilution of lipophilic materials in oils will lead to slow

release

of the material. Bioaccumulation following administration is also

related

to bioavailability and biochemical kinetics. Lipophilic toxicants

accumualte

and partition into lipid droplets and may be prevented from

biological

breakdown and against biological response until they reach high

levels that

the adipose cells within an animal cannot accumulate anymore or the

degradative systems become saturated so levels of the toxicant in

acqeous

compartments increase and evoke toxic responses.

Subject: Re:Question set 1. Questions arising out of the historical background of toxicology. Posted: Mar-04-02 at 6:04 PM by Kenneth Campbell View the history for this message Reply Edit the message Re:Question set 1. Questions arising out of the historical background of toxicology. Delete the message Re:Question set 1. Questions arising out of the historical background of toxicology.

Neetu:

February 19,2002

2. Bioavailability is an important factor when talking about biochemical kinetics. The amount of

dose absorbed by the systemic circulation is referred to as bioavailabilty. The concentration of

the toxin is as important as the dose of the toxin when dealing with toxins. The form of delivery

also plays a role because some ways are better than others to make sure that the drug enters

the systemic circulation.

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.

Discussions: Question Set 1. Question 7. Toxin Metabolism Considerations

Topic: Question Set 1. Question 7. Toxin Metabolism Considerations

Subject: Question Set 1. Question 7. Toxin Metabolism Considerations Posted: Mar-04-02 at 4:00 PM by Kenneth Campbell

7. Emphasis in the discussion of biochemical and physiological means of toxin metabolism and clearance is on the adult animal. Are there other important considerations or routes to be considered in growing offspring or during the reproductive process?

Posted: Feb-12-03 at 11:45 PM by Ivana Djuretic

For a developing fetus the major route of exposure is the placenta. Along with the nutrients, various toxins and toxicants that enter the mother via standard routes move across this barrier against a concentration gradient. Though this barrier could consist of multiple layers, their number is not of great importance for the rate of diffusion of chemicals. It is rather the solubility of toxicants that is important so if a toxicant was able to rapidly diffuse across other body membranes it will do so across the placenta. Luckily, 50-50 equilibrium is not always established between the mother and the fetus because fetal tissue is usually less developed and less able to concentrate the toxicant (exception: brain)

In addition to this, developing offspring can encounter toxicants postnatally (through lactation) as well as prior to conception (through seminal fluid). For this purpose many developmental and reproductive toxicity tests are available. Segment I tests evaluate the effect of chemicals on general fertility and reproductive performance; segment II tests administer chemicals during early pregnancy; segment III tests are done in late pregnancy and continue into lactation.

Posted: Feb-13-03 at 6:35 PM by Erin Valentine

In addition to the placental barrier, another important route to consider is the blood-testis barrier. This barrier prevents free exchange of chemicals/drugs between the blood and the fluid inside the seminiferous tubules. The barrier is composed of tightly fit epithelial cells, which may have sections with leaky junctions. Lesser-developed barriers in immature testes have more of this leakiness, thus leading to a greater chance for exposure. If a toxin does pass through this barrier, several mechanisms for metabolism exist in the testes. These include mixed-function oxidases, epoxide-degrading enzymes, gonadal cytochrome P450 and AHH present in microsomes. This metabolism, however, can have adverse effects on spermatogenesis and/or steriodogenesis. Metabolites of toxicants alter testicular structures resulting in deleterious effects to the germ cells. Examples of this include the oxidization product of n-hexane, 2,5-HD, which alters the microtubules in Sertoli cells ultimately preventing the paracrine support for the germ cells. Other toxic metabolites cause abnormal sperm, testicular lesions, decreased sperm mobility and damage to the Sertoli and Leydig cell functions (see C&D 689-690). All of these factors can be deleterious to the possibility of reproduction.

Posted: Feb-13-03 at 10:57 PM by Lisa McIntosh

Differences in a child's behavior and physiology are major factors that need to be considered when addressing toxicity. Children often have a much higher exposure potential (to environmental toxicants, in particular) than adults: they play in the dirt outside or on the carpet; they consume more food and water and have a higher inhalation rate per body weight; they orally explore their surroundings; they drink breast milk. Likewise, their uptake, metabolism, and excretion mechanisms vary from those of an adult. Because of their enhanced exposures, children are generally more susceptible to chemical insult than adults.

Posted: Feb-15-03 at 11:33 AM by Hanae Hiyoshi

Some routes of exposure which negatively effects on reproductive process are inhalation, ingestion of food and water containing toxin/toxicant, and skin. As an example, lead can be found in many kinds of food or in leaded paint. Lead is a tetratogen that can cause fetal malformation, a mutagen that can impair fertility and affect both sperm and eggs. Through inhalation lead is almost completely absorbed after entering lower respiratory tract, and it affects major organs in the body, especially children's nervous system. Its absorption rate through ingestion for young children is 4 to 5 times higher than for adults, causing lead poisoning and permanent neurological, cognitive impairments.

Resource: http://www.pca.state.mn.us/waste/listedmetals.html

Posted: Feb-16-03 at 6:24 PM by Michael George

In the growing offspring or developing fetus, a number of considerations need to be made. The growing offspring is more susceptible to toxicants due to its behavior as a young, i.e. it eats more, plays around and explores. Also, their methods of clearance, metabolism, detoxification, and excretion are not as developed as adults along with their immune systems. During development, the fetus absorbs nutrients from the mother from the placenta, so whatever toxicants the mother may be able to clear, the fetus may not be able to and absorbs it. Examples of this can include leaded paint, where in small amounts to adults is not toxic while can cause numerous developmental problems during development.

Posted: Feb-18-03 at 7:10 PM by DINA KATZ

First of all, embryonic and fetal development in mammals makes use of the placenta, which is permeable to many toxins and toxicants present in the mother's circulation, as well as viruses and other pathogens. If the pregancy happens at a difficult time for the organism, fat reserves may be mobilized, which may contain a significant amount of toxic substances that are then passed to the fetus. Fetuses and newborns often have underdeveloped metabolic pathways for clearing toxins and toxicants crossing the placental barrier or passed through mother's milk. Once infants are weaned at least partially, any other food is also a consideration, as it may contain substances harmful to the underdeveloped systems, which might go unnoticed in adult toxicity testing. The same goes for other routes of exposure: anything inhalable or in dermal contact with the baby which may be considered safe for adults may not be safe for the newborns. In addition, once children are mobile, they tend to ingest and come in contact with a wider variety of materials not intended for consumption or inhalation.

Teratogenic effects are also a consideration. When a toxicity study is performed, it may or may not be done on pregnant or impregnating animals; if it is not, there is no way to definitely rule out possible effects on the reproductive system even if the adult test subject exhibits no adverse effects whatsoever. It is also possible that a long-term effect exists, as a result of a slow metabolic pathway to the ultimate toxicant. For example, a rat injected with a potential toxicant is mated, say, three days after the injection, and the offspring exhibit no ill effect. However, a mating in two weeks will show severe teratogenic effects originally attributable to the injected substance.

Old

Allison:

February 20, 2002

7. Growing offspring and embryos developing during the reproductive process are more susceptible to the effects of toxins than the adult animal.

Biochemical and physiological means of toxin metabolism and clearance are usually focused on the adult animal but many studies have been performed that provide data on the vulnerability of growing offspring as well as the knowledge that most chemicals are not denied entrance into a number of compartments or secretions of the reproductive tract. This includes the placenta being unable to restrict and prevent most chemicals from crossing the placenta. Xenobiotic and certain drugs can be detected in uterine secretions, in the milk of lactating mothers, and in seminal fluid.

There also appear to be no specialized barriers to prevent chemicals or drugs from acting on the ovary.

Some important considerations and routes of delivery to be looked at in growing offspring and during the reproductive process are that tissues and bones have not fully developed and therefore do not have the ability to withstand toxins as in adults and to metabolize and secrete to eliminate

them before harmful effects can take place. Growing offspring do not have fully developed digestive or reproductive systems and are more susceptible due to protective mechanisms not being intact and fully developed.

Joanne:

February 20, 2002

7) YES! Teratogenesis (ie abnormal development) is evidenced by mutations, chromosomal breaks, altered mitosis, altered nucleic function, osmolar imbalance..etc..etc.. All of which may be triggered by toxic agents delivered through the conceptus at the cellular level, the insult may occur through a direct effect on the embryo/fetus, indirectly through toxicity of the agent to the mother and/or the placenta or through a combination of direct and indirect routes of entry ( C & D, page 365).

Also - a developing child will be differentially effected as a young child's nervous system is still

developing until approximately age 10. For instance, organophosphate insecticides, which are the commonly used product since the removal of organochlorines, have been found to differentially effect adults and children. Some of the typical cholinergic signs of bradycardia, muscular fasiculations, lacrimation and sweating were less common in children but seizures, lethargy and coma were most prevalent in children.

Because the toxic agent is acting on two different systems (ie developed vs undeveloped NS, a different result would be expected).

Neetu:

February 20, 2002

7. It is imporatnt to undesrtand the fetal metabolic pathways becuase offspring can be exposed

to chemical and physical agents that could result in adverse effect. This exposure can occur at

the time of conception, during pre and post natal development (until puberty is reached). yes,

important considerstions and routes should be considered in growing children becuase the

offsprings are still developing, and are not as developed as adults, and therefore, their body

works little differently than that of adults.

Topic: Question Set 1. Question 10. Risk Strategies & Levels of Toxicity

Subject: Question Set 1. Question 10. Risk Strategies & Levels of Toxicity Posted: Mar-04-02 at 4:04 PM by Kenneth Campbell

10. What distinctions might be made between lethality, morbidity, reproductive capacity, quality of life, and quality of environment impacts vis a vis risk assessment strategies?

Posted: Feb-12-03 at 12:11 PM by Erin Valentine

10. The distinctions between these categories of various levels of risks and the risk assessment strategies are that of result of exposure to a particular toxic substance. Assessing the risk of a lethal substance would include animal testing and determination of LD50 under a varying set of conditions, such as length of exposure, site of exposure, number of test subjects, etc. Assessing the risk of a morbid agent would require more specific testing. The observations would now have to include clinical observation of symptoms and postmortem examination to determine the site of action and characterization of the specific effect of the chemical. These observations may be the occurrence of tumors, damage to particular organs, or interruption of a biological function. In the case of assessing the risk to reproductive capacity, the tests must focus specifically on the endocrine and reproductive systems of the organisms. The tests to determine the reproductive toxicity of an agent are performed on rats through six stages described by the International Commission on Harmony, from premating to weaning and sexual maturity of the offspring (Klaasen 2001). Quality of life risk assessment would need to test the ability of the agent to affect a condition of life that does not cause death or disease such are skin and eye irritants. Quality of environment impacts risk assessment must test all of these conditions as well as the effect of the agent on the natural habitat. This assessment might include the effect of an air pollutant on the human population (lethality, morbidity, reproductive capacity, quality of life) and on the wildlife (LD50 of certain populations) and on the plant life (observation of decrease in growth).

Posted: Feb-14-03 at 9:58 PM by Lisa McIntosh

On an individual basis, the first three terms reflect varying degrees of toxicity: lethality, obviously, is the most severe; morbidity may ultimately decrease lifespan; reproductive capacity in and of itself may not adversely affect an individual, although could negatively impact a population through decreased fecundity.

Quality of life impacts may not necessarily result in harmful effects to an organism; however, that quality is degraded from optimal conditions. Nuisance odors- chemicals present at concentrations above the odor recognition threshold, but below deleterious levels-are a good example of this. In terms of risk characterization (in Massachusetts, anyway), the presence of nuisance odors indicates a condition of significant risk to public welfare exists (even if the contaminants may not present a risk to human health).

Quality of the environment, be it on a localized or global scale, ultimately determines the level of impact. Risk assessment is a tool by which we relate the quality of the environment to public health or the environment. The underlying premise is that there is an "acceptable" level of risk—such as allowing residual contamination to remain in the soil, using a drug for therapeutic effects despite the potential for side effects, or using household cleaners or pesticides that may be lethal if used incorrectly.

Posted: Feb-16-03 at 12:03 PM by ERIC FAULKNER

Risk assessment can be classified as a quantitative estimate of the potential effects on human health and the environmental significance of various types of chemical exposure (Klassen). In identifying a hazardous agent, tests are performed to determine if the agent will cause an adverse effect through structure activity analysis, in vitro testing, animal bioassays, and epidemiology studies. Additional testing is performed to determine the dose-response relationship and the duration of exposure to the hazardous agent in question. These assessments form a Venn diagram that make up the three categories of toxicological studies; mechanistic, regulatory, and descriptive. While lethality, morbidity, reproductive capacity, quality of life, and quality of the environment all play significant roles in the study of toxicology, further distinctions can be made by the following; lethality is an acute test first performed on a NCE with a fixed dose on a small population where an LD50 is determined. Morbidity can be considered a long term exposure study where a population is subjective to an agent for greater than 3 months where alterations on biological functions are addressed. Reproduction takes into consideration the effects of the reproductive system and the potential of the hazard to disrupt embryonic development. And furthermore, quality of life and quality of the environment assess the effects of a hazard on a large population and in nature where risk managers summarize the potential risks.

Subject: Re:Question Set 1. Question 10. Risk Strategies & Levels of Toxicity Posted: Feb-17-03 at 1:29 AM by Michael George View the history for this message Reply Edit the message Re:Question Set 1. Question 10. Risk Strategies & Levels of Toxicity Delete the message Re:Question Set 1. Question 10. Risk Strategies & Levels of Toxicity

Looking at individuals, lethality which leads to death, morbidity which leads to a decrease in lifespan, and reproductive capacity all are the most serious. The last one could end up affecting a population as a whole in the long run. Quality of life toxicity issues wont necessary affect the organism in harmful ways, but may cause degradation in the quality of life for the organism. For example a annoying smell may occur in the organism or a scar which may be unpleasant but won't probably lead to death. But, the presence of an odor in an area may lead to fears of something harmful even though there is no harmful toxicant. Quality of environment is looking at the safety of the environment as a whole. It is important for risk assessments because it allows us to keep the public informed to what is a safe level of risk for products that are toxic such as household products. Also in what are side effects for medicines.

Posted: Feb-17-03 at 7:09 PM by DINA KATZ

A risk assessment is an expert's opinion of the likelihood of a deleterious effect. Depending on what that effect might be, lethality(death), morbidity(disease), quality of life (level of comfort for the living organism), etc., the assessment will differ for the same toxicant. There may be a high risk of reduction in the quality of environment (how conducive the surroundings are to life) but not necessarily lethality. For example, an oil slick is a high risk for the beach by your house, but it carries a very low risk of death for you personally. Similarly, reproductive capacity of pond-living organisms may be severely reduced by a toxicant dumped into their pond, but have no effect on their own quality of life. Assessment strategies would thus have to be tailored to estimate the risk to a specific effect (i.e. if it is necessary to carry out an assessment of morbidity of tadpoles in Lake Erie, one should probably observe behavior and collect some specimens and inspect their tissues, rather than spend time observing a reproductive cycle and counting young.)

Posted: Feb-18-03 at 4:23 PM by Ivana Djuretic

Risk assesment strategies require the following components:

-hazard identification-an evaluation of the adverse health effects the agent is capable of causing: damage to liver, nervous system, carcinogenesis

-dose response assessment-includes prediction of exposure levels at which risk is likely to be negligible or nonexistent

-exposure assessment - a determination of how much of an agent people might be exposed to under various conditions such as use of a drug or a consumer product, environmental exposure at a hazardous waste site.

-risk characterization- explicit description of the assumptions and uncertainties that go into the risk assessment, and the overall confidence in the results of the analysis.

It seems like risk assesment strategies will only characterize lethality of a substance with a high degree of certainty (even then there is genetic variability) but that for other levels of toxicity it will be extremely hard to predict the levels of risk. Even for a simpler task such as cancer assessment, mathematical models are needed to connect the results of experiments with a limited number of animals to large scale predictions (more than 1 additional cancer in 1 million exposed people is unacceptable risk, but you cannot test 1 million animals). So morbidity, reproductive capacity, quality of life and environment differ from lethality in the certainty of risk predicted by risk assesment strategies.

I will use this question to comment on the ambiguity of the assigned questions (some, not all). I found it really hard to formulate an answer to this question without just defining what lethality, morbidity etc is, or giving the type of tests that one would do to assess lethality, morbidity, etc, but that doesn't seem to be what the question asks. Even after reading Ch 4 and doing some additional research I couldn't describe in one simple answer how risk assesment strategies would distinguish between all those different categories of toxicity. The answer seems to be the entire of toxicology. Is anybody else having problems with the nature of the questions? Maybe we are unable to start threaded discussions because people are interpreting the questions in different ways and its hard to agree or disagree with someone talking about an entirely different thing than yourself. Again it could be just my view, but I'm almost sure that having more specific questions would spark a discussion less vague.

Posted: Feb-20-03 at 10:29 PM by Diana Esshaki

The variety of adverse effects of chemicals on humans clearly impacts risk assessment strategies. Bioassays and LD50 aid in developing these strategies. When assessing risk of toxins, lethality (ability to cause death), morbidity (ability to cause disease), reproductive capacity, quality of life, and quality of envronment do have distinct impacts on determining risk. In this case, since the question is quite vague, it is probably more helpful to look at an example: mold spores.

(Radiation is actually a more clear cut example, however, I am assuming that we aren't considering that a toxin.)

Lethality: Clearly the most significant factor does not play much of a role with mold spore exposure. Put another way, when assessing risk, this "toxin" does not cause death.

Morbidity: Exposure to mold (esp.indoor constant exposure) can cause a wide array of health problems. Very large doses of mold spores (inhaling or ingesting) can result in poisoning by mycotoxins. Exposure can cause allergic illnesses, asthma, and infection (lung or respiratory tract). In this case, morbidity has a very high and quite distinct effect on risk assessment.

Reproductive capacity: Mold spores are not usually a health risk factor on repro.

Quality of life: Mold spores indoors can not only cause a health risk, but can make living uncomfortable by adhering to ceilings, etc. in the home.

Quality of environment: Varies depending on indoors vs. outdoor exposure- indoor causing more direct inhalation and infringing on safety of the individuals exposed.

Old

Allison:

February 20, 2002

10. Risk assessment strategies are definetly impacted by differences between lethality, morbidity, reproducing capacity, and quality of life and environment. In determination of the risk of a toxin, acute testing would be performed on toxins that my be considered lethal. Morbidity involves a compromise of function, including, disease rates, genetic defects, and toxicant effects, all of which may not be lethal. In testing whole populations, reproductive capacity and morbidity may lead to lethatlity, which is very damaging and would be considered in those risk assessments.

However, when looking at individuals rather than a species as a population, morbidity , reproducitve capacity, as well as, quality of life and environment may not be extrememly toxic in the sense that one can still survive. Toxic effects exist at various levels and when assessing risk of a toxin, it is possible that they will not induce effects that generate lethality of morbidity but will alter quality of life and/or environment. In these cases, the strategy about how assess risk changes and preventing death is no longer a goal, but instead preserving a quality of life and

general well being.

Joanne:

February 20,2002

10) Lethality: death

Morbidity: diseased state, decreased life span

Reproductive capacity: ability to reproduce

Quality of Life: nonmedical threats that compromise one's ability to enjoy life

Quality of environment: degree of safety, comfortability and security in surroundings

In terms of these factors with respect to risk assessment strategies, they are ordered in terms of

importance with the greatest stressor on lethality and in descending significance thereafter.

Obviously,lethality would have the greatest influence on risk assessment. Although there may appear to be an element of subjectivity (ie reproducitve ability vs quality of environment..etc..etc), overall they are ranked in accordacne with what the majority of individuals would assess in terms of personal importance.

Neetu:

February 20, 2002

10. Lethality is related to death, morbidity is related to compromise in functionality. In individual lethality, it is not necessary that it means inability to reproduce. When talking about population lethality, th emorbidity might be lethal. The toxins might change one;s quality of life or living standards but it is not necessarily lethal. The quality of environment will effect each individual differently.

Topic: Question Set 2. Question 6. Oral Toxicity Paradox

Subject: Question Set 2. Question 6. Oral Toxicity Paradox Posted: Mar-04-02 at 6:54 PM by Kenneth Campbell

6. Oral toxicity studies have defined a paradox of this route of exposure. What is the paradox and how might it be explained? A somewhat similar paradox can arise if dietary insoluble fiber is high and exposure is again oral. Why might this occur? Are either of these situations of possible use in treating acute poisonings? In chronic intoxications?

Posted: Feb-13-03 at 8:58 PM by Erin Valentine

The paradox of oral toxicity studies is that the absorption of a substance depends on a number of variable factors. Organic acids and bases are absorbed in the section of the GI tract where they exist in the nonionized form. The acidic environment of the stomach versus the neutral environment of the intestine can markedly affect the ability of a toxin to be absorbed. Differences in surface area of the stomach, small intestine and large intestine also influence aborbancy, larger surface areas generally allowing for more opportunity for absorption. Another factor is that a number of toxicants are biotransformed in the GI tract into substances with either increased or decreased toxicity. The time a toxic agent spends in the GI tract can also influence absorption, the longer time spent, the more opportunity. Here is where dietary insoluble fiber can come into play. If the level of insoluble fiber is high, then movement through the GI tract is faster, thus decreasing the opportunity of a toxin to be absorbed. These situations can be used to treat acute poisonings by capitalizing on the absorptive properties of poison. If the nature of the poison is known, administrating ions that prevent the absorption could be used as a treatment. Another tactic may be to administer a substance that would decrease the solubility of the substance. If the poison cannot be dissolved, it won't be absorbed. The property of dietary insoluble fiber could be used to flush out the poison from the GI tract by essentially pushing it through before it could be absorbed at high enough concentrations to exhibit a toxic effect.

Posted: Feb-14-03 at 10:00 PM by Lisa McIntosh

The paradox is that the oral route of exposure is probably the most common route (e.g., accidental or intentional ingestion), and intuitively seems like it would be the most direct route to toxicity, but toxicity generally will not occur through oral exposure until the toxicant is absorbed into the body (with the exception of caustic materials). In principle, this is not very different from dermal exposures-a chemical would have to penetrate the skin and be absorbed into the bloodstream in order for toxicity to result. Thus if absorption can be inhibited within the gastrointestinal (g.i.) tract, toxicity may be reduced or eliminated. Numerous factors influence a toxicant's absorption in the g.i. tract: pH, surface area, active and passive transport, pinocytosis, etc.

Regarding insoluble fiber, ingestion of fiber increases the rate at which a bolus is passed through the gut, thereby reducing the amount of time available for exposure, and by extension, reducing absorption. Therefore, if a toxicant is delivered to the gut coincidentally with another substance that either increases g.i. elimination rates or inhibits absorption of that toxicant, toxicity will be reduced. For acute poisonings, this would be (and is) an effective antidote. For chronic exposures, it may be also be beneficial, as in the case of insoluble fiber. One problem that I can foresee, however, is that chronic administration of certain substances that may regulate absorption of a toxicant may also decrease absorption of beneficial compounds (Olestra, anyone?).

Posted: Feb-17-03 at 7:03 PM by Ivana Djuretic

I am not sure about other substances that regulate absorption but in the case of dietary fiber continuos exposure is extremely beneficial. In the diets of many third world cultures between 150 and 175 grams of fiber is consumed daily (only 30 for US). Accordingly, they are not plagued with most of the "industrialized" disorders which include colon and breast cancer, heart disease, diabetes, arthritis, chronic fatigue syndrome, weakened immune systems, personality disorders, and all of the hormone-based female disorders. Most experts now agree that these nondigestible carbohydrates promote not only laxation, but blood cholesterol and glucose attenuation as well. The latter two functions are promoted by soluble fiber. Soluble fiber reduces cholesterol by reducing its absorption in the intestine and by complexing with bile acids (made from cholesterol in the liver) and preventing their reabsorption (so that liver must use additionnal cholesterol for making more bile acids). Soluble fibers also help normalize blood glucose levels by slowing the rate at which food leaves the stomach and by delaying the absorption of glucose following a meal. They also increase insulin sensitivity.

Insoluble fiber, as mentioned before, helps maintain bowel regularity by increasing the bulk of the feces and decreasing the transit time of fecal matter through the intestines. Bowel regularity is associated with a decreased risk for colon cancer and hemorrhoids. Additionally, fibers have been shown to have a gentle brooming effect on the inner walls of the intestines, performing what might be called "daily house cleaning." They have a binding effect on toxins in the colon, as well as harmful estrogen metabolites, excess dietary fat and cholesterol, so they are able to assist in the rapid excretion of these materials, thereby blocking their re-absorption into the bloodstream. Research has shown that heavy metals, such as lead and mercury, are excreted harmlessly and much more efficiently when pectin (a type of fiber) is included in the diet. Apple pectin, rice bran, wheat bran, alfalfa fiber and burdock root fiber, along with other sources of dietary fiber, have been shown to protect the body, and especially the gut, against the toxic effects of several common food additives, including amaranth, Tween 60, sodium cyclamate, tartrazine, and Sunset Yellow.

Taken all of the above into account, chronic exposures to many toxins/toxicants CAN be treated by continuous, moderate intake of fiber. Only large amounts of fiber taken continuously were found to partially block the digestion, absorption or reabsorption of a wide variety of drugs and fat soluble vitamins. Taking twice as much fiber as is recommended (~50 grams daily) will improve rather than compromise our health.

Posted: Feb-17-03 at 8:57 PM by Lisa McIntosh

I couldn't agree more in the case of insoluble fiber-but I was suggesting, rather, that perhaps other substances (not noting any specifically) that may inhibit uptake of toxicants into the gi tract to treat chonic exposures may possibly have a negative effect on absorption of essential nutrients. I gave the example of Olestra, a synthetic fat that is not absorbed (and therefore is 'calorie-free'). However, it was noted that certain nutrients were also not absorbed. In the long-term, reduced absorption of essential nutrients will be detrimental to an organism's health.

Posted: Feb-19-03 at 11:59 PM by Ivana Djuretic

References for the above question were:

http://www.health-science.com/index.htm?page=/fiber.html

and

http://www.springboard4health.com/notebook/nutrients_fiber.html

Posted: Feb-15-03 at 8:06 PM by Hanae Hiyoshi

Oral toxicity may involve transmucosal absorption and also chemical modification in the stomach acid, which degrades and hydrolyze the compound to make it easily degraded or absorbed. The paradox is that the body of animals, including humans, does not really resist toxic materials until they enter into the bloodstream. Most of animals have "oral tolerance"—the immune system of the animals does not recognize potential immunogens if they are exposed orally in their childhood. Through an oral route those organisms invade the animal's intestinal tract and grow inside white blood cells without being killed.

Insoluble fiber, such as cellulose, homicellulose and legnin, can be found in food like wheat bran and is useful in weight control because it gives us a fullness feeling. It is not broken down by digestive enzymes and could be useful for treating acute poisoning because it slows digestion, reduces metal absorption, and speeds up bowel elimination processes. Intoxication occurs when waste in the bowel is trapped for a longer while, causing toxins to go back into the colon. The toxins then eventually go into the bloodstream through the blood capillaries along the bowel wall and harm other organs and cells. Insoluble fiber can help foods keep moving the digestive tract, reducing potential carcinogens in the colon.

Posted: Feb-17-03 at 7:17 PM by Ivana Djuretic

Other answers have described in detail the paradox of the oral toxicity and pointed at intestine as the main site for entry of xenobiotics. Under normal conditions, xenobiotics are poorly absorbed within the mouth and esophagus, due mainly to the very short time that a substance resides within these parts of the GI tract. There are some exceptions though. Nicotine readily penetrates the mouth mucosa and nitroglycerin is placed under the tongue for immediate absorption and treatment of heart conditions. The sublingual mucosa under the tongue and in some other areas of the mouth is thin and highly vascularized so that some substances will be rapidly absorbed. Very little absorption takes place in the colon and rectum. As a general rule, if a xenobiotic has not been absorbed after passing through the stomach or small intestine, very little further absorption will occur. However, there are some exceptions, as some medicines may be administered as rectal suppositories with significant absorption. An example, Anusol is used for treatment of local inflammation which is partially absorbed (about 25%). Reference: http://www.sis.nlm.nih.gov/ToxTutor/Tox2/a22.htm

Posted: Feb-18-03 at 9:56 PM by DINA KATZ

A paradox in the po route of exposure lies in the fact that a chemical passes through several environments (the mouth, esophagus, stomach, small, then large intestine, rectum), most of which are lined with mucosal layers and are functionally geared to eliminate the contents. The stomach and small intestine also radically change the pH of their contents, likely biotransforming the initial toxicant. Thus, most poisons do not do much damage in the alimentary canal, but only once they are absorbed from there into the bloodstream, even if they are broad cellular mechanism disruptors such as cyanide, which blocks the final step in the electron transport chain in aerobic respiration. Insoluble fiber promotes a speedy passage through the intestines and has, as someone mentioned, a "gentle brushing effect" on the walls, thereby removing mucosal cells that already contain the poison and would allow it to diffuse deeper and closer to the bloodstream. Though one might intuitively think that fiber "stops up" the flow as it does in a sink, it in fact promotes elimination. The faster the flow, the less material will get absorbed in the alimentary lining.

This idea has an obvious application in acute poisoning cases: after such an event, a good quick treatment might be a fast-acting laxative, such as syrup of ipecac. Vomiting may or may not be a good idea; although elimination from the body might be faster, the ingested contents may no longer be in the stomach, and the esophagus does not have much lining, so it may be damaged by a corrosive poison twice (up and down). Drinking large amounts of water would probably not be a good idea, since water is mostly not eliminated through the bowels, but enters circulation and goes through the liver and kidneys at the very least. I don't see how it can help clear the GI tract, but I could be wrong. Anyone?

In chronic (6 months to 2 years) intoxication cases, the technique is not likely to help. I suppose it's possible that if the poison is extremely slow to absorb, intake of insoluble fiber would help clear the outer mucosal layers where much of the toxicant would still linger.

Old

Allison:

February 28, 2002

6. One of the main sites of absorption is the GI tract. Many environmental toxicants enter the food chain and are absorbed together with food from the GI tract. Unless a noxious agent has caustic or irritating properties, poisons in the GI tract usually do not produce systemic injury to an individual until they are absorbed. Absorptions of toxicants can take place along the entire GI tract, even mouth and rectum. There are factors though that alter the GI absorption of toxicants and serve as a paradox in these studies. The mass action law, surface area, and blood flow rate have to be taken into consideration. Some studies have shown that oral toxicity of some chemicals is increased by diluting the dose. This can be explained by more rapid stomach emptying induced by increased dosage volume, which in turn leads to more rapid absorption in the duodenum because of the larger surface area there. There is also a species-dependent absorption different of toxicants due to the gastrointestinal flora. It dietary insoluble fiber is

high and exposure to a toxicant is oral, some of the smae problems might arise. The toxicant may not produce any deleterious effets until once it has absorbed into blood at the time of elimination. Acute poisonings might be treated by this situation if the insoluble fiber can absorb the toxicant and prevent absorption into the bloodstream during elimination. Chronic intoxications might be more difficult to treat because continuous exposure to the toxicant will ultimately be hazardous to the liver and be unable to be eliminated before deleterious effects take place.

Neetu:

February 28, 2002

6. The paradox is the change in level of toxicant's absorption into the blood stream and the

interference of toxicant with other minerals (if talking about insoluble fibers). The toxins that pass through the GI tract (main path taken when dealing with oral toxicity), do not cause any toxicity until they are absorbed into the blood stream, which might take some time. A somewhat similar paradox can arise if dietary insoluble fiber is high and exposure is oral. Insoluble dietary fibers include cellulose, hemi-cellulose etc. It is mostly found in whole grain products such as wheat bread and is known to induce bowel movement. Insoluble fibers speed up the passage of food via the GI tract, promote bowel movement, slow down the breakdown of starch and delay the absorption of glucose. Fiber is not toxic; it can however, interfere with other mineral absorption, if the intake go above the recommended level (20-35 g/day). TOO much fiber intake can also result in too much calories intake and therefore, can cause intestinal discomfort and excess gas formation

(http://www.solae.com/NASAPP/solae/soy nutrition/nutrition basics/necessarynutrients/no nutrients.jsp). The acute poisoning can be treated because the exposure of the toxicant is for a short period of time and the toxicant might not be absorbed by the blood stream just yet. But the chronic poisoning might be hard to treat because of the longer exposure time and the toxicant will be able to absorb into the blood stream and cause deleterious effects.

Joanne:

February 28, 2002

6) A paradox in the oral route of exposure is that of the alimentary canal. It is the route that serves both digestion and respiration…that in and of itself is a blatant paradox. In terms of toxicity however, the coupling of food which is required for maintenance and sustenance of the organism, may also be threatened by inadvertently intaking toxins/toxicants into the GI tract. Many environmental toxicants enter the food chain and are absorbed with food from the GI tract ( C & D page 111). Although the GI tract is within the body, its content may be considered "exterior" to the body thereby not typically producing injury following the entrance of noxious agents until they are actually absorbed. Absorption can take place "anywhere" along the GI tract (ie mouth to rectum) depending on the chemical composition of the toxic agent in question.

For example, if it is an organic acid/base, it is usually absorbed by simple diffusion at the point

where it manifests its most nonionized form. An additional paradox exists when thinking about

digestion/respiration as routes of oral entry. For the absorption of toxic gases in the lungs differs from intestinal and percutaneous absorption of compounds in that dissociation of acids and bases and the lipid solubility of molecules are less important factors in pulmonary absorption because diffusion through cell membranes is not the rate limiting step as it was in the GI tract ( C & D 115).

Different species have different types of digestive systems. Some are more capable/efficient at breaking down food products than others. Others may be less efficient and less capable of breaking down certain food products. Those with efficient systems may quickly rid themselves of a food product while others may store these products in their less than optimal systems.

With respect to question #6 and the case of insoluble fiber:

With the increase of insoluble fiber,a decrease in gut transit time would be expected because fiber is able to bind to steroid compounds in the lumen facilitating their excretion. The decrease in gut transit time would seem to lessen intenstinal absorption of compounds in the gut. Such reduced absorption, limits the availability of a compound to travel through enteroheptaic circulation and results in the increase of the original compound deposited in solid waste products and decreases the amount in urine and infiltrating metabolites. Because less of the xenobiotic compound is traveling through enterohepatic circulation, less hepatic filtering may contribute to

a reduction in the polarity of metabolites excreted. By tracking such steroidal components may prove to be beneficial markers in tracking carcinogenic properties. Whether acute or chronic depends on the individual digestive system and the alteration of the ingested compound in question. For instance some fibers contain estrogenic or anti-estrogenic effects..Consumption of certain fiber substances may reduce the risk in developing certain types of cancers by reducing the risk of tumor growth which is often fostered by steroid compounds.

Topic: Question Set 3. Question 4. Time, dose, shielding.

Subject: Question Set 3. Question 4. Time, dose, shielding. Posted: Mar-07-02 at 3:15 AM by Kenneth Campbell

4. In radiation protection there are three cardinal rules for minimizing radiation exposure:

1. minimize time of exposure to the source

2. maximize distance from the source to minimize dose delivered

3. optimize the amount and type of shielding used to minimize dose delivered.

Can these be translated into considerations in toxicant exposure? What are the analogs of time, dose, and shielding for chemical exposures? Are there any differences among routes of exposure or nature of toxicant that need to be considered?

Posted: Feb-12-03 at 12:12 PM by Erin Valentine

4. These three cardinal rules can definitely be translated into considerations in toxicant exposure. The analog of time in chemical exposure is the duration and frequency of exposure. This includes the concepts of acute, subchronic and chronic exposure. The analog of dose is the applied amount of the toxic agent (mg agent/ kg test subject) that an individual is exposed to or more specifically the concentration of the agent at the target site. The analogs for shielding for chemical exposure include mechanisms for preventing absorption, presystematic elimination by biotransformation at exposure sites (lungs, stomach, skin), and prevention of agent's function through inhibitory binding. Shielding could also come in the form of protective gear specific to the route of exposure for the particular toxicant. The nature of the toxicant needs to be considered if the effect of the toxicant is increased by certain conditions. If the delivery of the toxicant were facilitated within the system, then the dosage amounts would be increased. Also if the toxicant were held in an inactive state after exposure until particular conditions released it, then the timing of exposure would also be altered.

Posted: Feb-13-03 at 6:53 PM by Ivana Djuretic

Depending on the route of exposure biological responses to a toxicant will differ/its toxicity changes. A chemical may be severely toxic by inhalation but not toxic by oral or dermal exposure. Differences in toxicity arise due to several factors:

-Rate of absorption- this will depend on the nature of the toxicant. Main sites of absorption are GI tract, lungs, and skin. Lungs are generally more penetrable for volatile compounds such as gases, vapors and aerosols. Skin is impermeable to many chemicals but not to nerve gases, carbon tetrachloride etc. GI tract absorbs a range of molecules:lipophilic molecules by simple difffusion and hydrophilic molecules by active transport or by passing through aqueous pores at the tight junctions.

-Availability of sites- because of a large surface area (size of a tennis court ) lungs are generally the most available site of adsorption)

-Presence of degradative enzymes-liver detoxifies many chemicals so LD50 for a given toxicant decreases if given via portal circulation (goes to liver) than via inhalation (systemic circulation). Degradative enzymes are also present in stomach and intestine. For instance snake venom is much less toxic if given orally rather than IV because it is broken down by digestive enzymes in the GI tract.

-Extreme conditions- newborns have a higher pH in their GI tract which allows for conversion of nitrates to nitrites and leads to a condition called methemoglobinemia (defect in oxygen transport)

-Rate of transit through the body- the slower the movements of the GI tract the more absorption.

Posted: Feb-13-03 at 10:40 PM by Lisa McIntosh

In terms of toxicant exposure, these same three rules likewise hold:

1. Minimize the time of exposure to the source. If you reduce your exposure frequency and duration, you reduce your risk of harm.

2. Maximize the distance from the source to minimize the dose delivered. In other words, avoid exposure, if possible. No exposure is equivalent to no toxicity.

3. Optimize the amount and type of shielding used to minimize dose delivered. We can reduce exposures further by wearing protective equipment (e.g., gloves, respirators, goggles) or by other measures such as washing exposed surfaces following contact.

When working with radioactive materials, dermal penetration of rays is probably one of the greater concerns; however, a radioactive compound, as with any compound, can enter the body through various routes of exposure-ingestion, inhalation, via injection, etc.

Posted: Feb-15-03 at 4:14 PM by ERIC FAULKNER

As ionizing radiation passes through a substance it will lose energy, due to the fact it produces an electron and a positively charged atom residue. When humans are exposed to radiation for certain periods of time, DNA synthesis becomes disrupted as the radiation breaks apart the precursors of DNA replication (purines and pyrimidines molecules). The following cardinal rules for minimizing exposure to radiation can be translated into considerations to toxic exposure because they somewhat pertain to an individual dose response curve (1) Deficiency and Toxicity will occurs with no protection from the radiation source and (2) Region of Homeostasis will occur with protection form the radiation source.

The analogies or similarities that exist would be time is to the frequency of exposure to radiation, the dose would be considered the intensity (delivered dose) of the radiant rays from the distance you stood from the energy source (closer you are the greater the intensity), and shielding exposures would be the protective garments worn to protect the skin and mucosa from absorption and distribution to the target site (DNA). Differences need to be consider among the nature of the toxicant rather than the routes of exposure. There are four main types of radiation, due to; alpha particles, electrons, gamma rays, and X-rays (Klassen). While the frequency and dose of radiation given to take pictures of teeth and broken bones is suitable to patients for X-rays, it would be determinantal to patients if gamma rays were used.

Posted: Feb-16-03 at 3:37 PM by DINA KATZ

The radiation exposure rules can definitely be translated into toxicant exposure rules. For chemical exposure, time of radiation exposure is analogous tob the amount of chemical one is being exposed to, since the more time one spends exposed to radiation, the more particles have the potential to hit the body. The dose is analogous to the toxicity of the chemical, the relative speed and amount of damage done at target sites, or possibly route of exposure, since that will control how much of the chemical will get inside the body. Shielding can be compared to either the effectiveness of detoxification processes in the body or the physical barriers preventing the toxicant reaching the target site.

Since toxins and toxicants are so different from each other in their mechanisms of toxicity, any of the three above variables may be the crucial step in preventing the most damage. For example, for highly toxic materials that do not easily detoxify in the body, 'shielding' takes on a much greater importance. For chemicals of relatively low toxicity, limiting the 'time' or concentration factor may prevent major damage.

Posted: Feb-16-03 at 5:02 PM by Michael George

Yes, these can be translated into consideration in toxicant exposure.

1.) Minimize time of exposure to the source-if you can reduce the amount of time you are exposed to a toxicant you can possibly avoid toxicant effects since your body may be able to eliminate the toxicant in small doses.

2.) Maximize distance from source, if you can avoid the toxicant than no toxic effect will be produced.

3.) Optimize the amount of shielding to minimize dose-using goggles, face masks, gloves, etc. can minimize the amount of toxicant received.

Yes there are differences among routes of exposure or the nature of the toxicant that need to be considered. In radiation there are basically just one way of exposure, via x-ray exposure through the skin. In toxicant exposure there are a number of different routes that need to be considered, ie. Subcutaneous, intravenous, inhalation, etc. Toxicants can be a a number of different forms also, ie solid, powder, liquid, gas.

Old

Posted: Mar-11-02 at 12:07 PM by allison gold

The three cardinal rules for minimizing radiation exposure can be translated in toxicant exposure. Minimization of time for toxicant exposure reduces the time available to act on the toxicant's targets and primiary molecules. The ability of the toxicant to bind and act on targets is minimized by minimizing time, as in radiation exposure as well. Maximizing distance of a toxicant relates to dose/potency/concentration. By maximizing distance from source of toxicant the dose/potency/concentration are minimized. Intensity of toxicant is inversely proportional to the distance squared. Toxicants can be minimized by optimizing sheilding. This includes limiting the routes of exposure available to the toxicant. Vaccines may also act as an internal shield, which will optimize endogenous barriers or repair processes (Campbell, Lecture 3/7/02).

Posted: Mar-11-02 at 2:32 PM by Kenneth Campbell

Please elaborate on your last comments.

Posted: Mar-14-02 at 6:19 AM by joanne vannah

Analogs in chemical exposure:

1) (minimizing time) Decrease in time allotted for binding on targets, we had recently discussed the GI tract and how toxic effects occur only after they are absorbed, by limiting the time factor, one decreases the degree of absorption, thereby lessening the toxicity effect.

2)(maximizing distance) Since the intensity of the toxicant is inversely proportional to the distance squared. The increase in distance of the toxicant from its target cell will certainly have a compromised effect in terms of potency and concentration.

3)(shielding) This may be accomplished by limiting the amount/dose, limiting the exposure routes, dilution may be helpful in some cases and interaction with other chemicals may decrease the effect.

Posted: Mar-11-02 at 12:10 PM by allison gold

(con't)

There are also differences among route of exposure or nature of toxicant that need to be considered in minimizing toxicant exposure because limiting access to one route of exposure that is known to be a risk for toxicants may make another route of exposure more accessible to the toxicant after chronic response.

Posted: Mar-12-02 at 1:57 PM by neetu kainth

#4

yes, these rules can be translated into considerations in toxicant exposure. Minimizing time means loweing the time od toxicant to interact with its target molecule. Dose/Potency/ Concentration can be a analog of dose and limiting routes of exposures via vaccines; optimize endogenous barrier of repair processes can be analog of shielding for chemical exposure. Well just like with any other toxicant; you want to choose a route of exposure that will not take a long time to eliminate that toxicant. You also want to choose a toxicant that can be easily discarded by the body. Here, we are talking about radiation, therefore, we have to be little more careful than if we are talking about some kind of drug because radiation can cause mutations rapidly and thereore, can cause developmental defects. Also, depending on the nature of the toxicant, you want to choose the route of exposure taht is limited and will easily eliminate the toxicant. For example, if the toxicant can be degraded in liver, you wnat to choose the route of exposure that is limited to liver only.