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.