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.