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TOXICOKINETICS

Absorption

Toxicokinetics involves absorption, distribution, metabolism and excretion of a chemical. Data regarding toxicokinetics of PCBs in humans have been derived predominantly from cases where subjects ingested contaminated food and from cases of occupational exposure via inhalation and dermal exposure. Oral, inhalation, and dermal routes of exposure, all contribute significantly to the absorption of PCBs.

Inhalation:

While inhalation absorption data are insufficient to determine absorption rates, inhalation is considered a major route of occupational exposure to PCBs.4 Additionally, there is indirect evidence suggesting absorption of PCBs via inhalation from observational studies of humans in occupational settings where air concentrations have been measured. These studies detected individual PCB congeners in both tissue and in body fluids.

Quantitative data suggesting absorption by this route varies in significance, but data summarized by Wolff (1985) suggest that as much as 80% of levels commonly seen in the adipose tissue of exposed capacitor workers may be due to inhalation. At the very least, absorption due to inhalation should be considered.

Oral:

Oral exposure through the consumption of food is believed to be the predominant route of exposure to PCBs for the general population. Contaminated water and soil impose an additional threat of PCB exposure on those near hazardous waste sites. 1994 estimates of PCB exposure for the contemporary UK claimed that approximately 97% of PCB exposure for the general population was due to food consumption. PCB contaminated fish, milk and dairy products, vegetables, and meat and animal fat accounted for 32, 26,18, and 16% of this exposure respectively. Vegetables are believed to account for most of the lower chlorinated PCBs while fish, dairy products, and meat contribute most of the higher chlorinated PCBs.

In the GI tract, PCBs are absorbed on a congener specific basis. They enter the body by passive diffusion. Therefore, a large concentration gradient with high levels of PCBs in the gut and very low levels in serum lipids will yield nearly complete absorption. Hence, absorption of PCBs is not only congener specific, but also depends on PCB serum concentrations, or the congener specific body burden which generally increases with age. Once in the blood, PCBs are carried by lipoproteins and, due to the lipophilic nature of these congeners, they accumulate in lipid rich tissue with greater relative amounts usually found in the liver, adipose, skin, and breast milk. A study by Schlummer et al. (1998) highlights the inverse relationship between absorption and blood serum levels (SEE FIGURE BELOW).

Direct evidence suggesting PCB absorption from oral exposure has been documented by human studies where subjects voluntarily consumed radio labeled PCBs. Studies of nursing infants have been documented as well, where the source of PCBs was the breast milk from the nursing mothers.

Indirect evidence suggesting absorption orally has been provided by studies of contaminated food ingestion by the general population. Elevated PCB levels in serum and breast milk were found in women who consumed contaminated fish from Lake Michigan. These women displayed a 52-62% increase in serum PCB levels five hours after ingesting the fish. Levels returned to normal seventeen hours later


Dermal:

While not a major concern for the general population, dermal absorption is recognized as important to the accumulation of PCBs in adipose tissue of workers in the capacitor manufacturing industry. Wipe samples taken from the face and hands of employees at a private utility company yielded PCB levels from 0.05-5mg/cm2. Assuming 100% absorption, these exposure levels would account for up to 20% of the adipose PCB levels seen among capacitor manufacturing workers.

In vitro studies utilizing human cadaver skin provide evidence of absorption, but only report findings on skin retention of PCBs. In order to study systemic absorption in addition to skin retention, animal studies have been conducted yielding varying results. Additionally, the in vitro studies suggested absorption dependence on the vehicles of exposure while the in vivo studies suggested that the vehicle of exposure had little effect on absorption. While the experiments yielded only slight practical value to the study of dermal absorption of PCBs, the results provided sufficient evidence that this route of absorption could be significant. .

Distribution

Data regarding the distribution of PCBs in human tissues and body fluids come mainly from studies of people exposed to PCBs in an occupational setting or from studies of those who have ingested contaminated food. Generally speaking, the main exposure routes in occupational settings are inhalation and dermal routes, while the main exposure routes for the general population is oral.

There is usually an initial uptake of PCBs in the liver and muscle due to the high blood perfusion in the liver and the relatively large amount (volume) of muscle. Subsequently, the distribution of PCBs in humans depends on the structure and physicochemical characteristics of the various congeners and is also dose dependent. The absorbed PCBs can either be excreted or retained in adipose tissue, skin, specific tissue (organs such as the liver, kidney, muscle, adrenal, lungs, or spleen) on a lipid basis, or in body fluids. Typically, less chlorinated congeners are readily metabolized and excreted. Conversely, highly chlorinated congeners are metabolized very slowly and tend to store in adipose tissue. Due to its high fat content, human milk can also accumulate large quantities of PCBs, which are passed along to children through breast-feeding. Additionally, biotransformation of PCBs can yield hydroxylated metabolites that are retained in the blood.

PCBs have also been detected in ovarian follicular fluid ranging in concentration from 0.5-24.2mg/kg, in sperm fluid from 1.8-58.6mg/kg, and in bone marrow from 2-4mg/kg (based on dry lipid weight). Nonetheless, most accumulated PCBs lie within adipose tissue or specific tissue (on a lipid basis) and in body fluids with average concentrations of 0.5-4ppm total PCBs being reported in milk fat, 0.5-10ppm in adipose tissue, and <5ppb in blood plasma

Metabolism

Metabolism of PCBs is the rate limiting step in the elimination of the toxic compounds so the biological half life of a congener depends on the body’s ability to metabolize it. The liver is the primary site of PCB metabolism, which occurs by hydroxylation and conjugation with glucuronic acid and sulfates. Generally, PCB’s with more than five chlorines and para-chlorine atoms are less susceptible to hydroxylation and show the longest half lives. These PCBs can bioaccumulate withing the body. PCBs with chlorine-unsubstituted meta-para-carbons are more susceptible to hydroxylation with PCBs of greater than five chlorines being relatively less susceptible. Typically, the metabolism of xenobiotics yields polar compounds that can be cleared from the body, but several PCB metabolites are retained in the body displaying biotransformation into a secondary class of environmental toxicants. A better look at the mechanism of hydroxylation will help to clarify this (SEE FIGURE BELOW).


from the Handbook of Environmental Chemistry vol 3. part K, pg320, 2000 29

Hydroxylated metabolites are the predominant products with hydroxylation occurring at unsubstituted para and meta positions. Hydroxylation can occur via direct insertion in a meta position or by formation of an arene oxide intermediate, a process mediated by the cytochrome P450 system (CYPs). The arene oxide intermediate then rearranges to a hydroxy group. Some OH-PCBs (formed either by direct insertion or by arene oxide intermediate) are persistent within the body and are retained in the blood. Other OH-PCBs can be further metabolized in a conjugation reaction with glucoruonic acid or sulfate. This conjugation increases the water solubility of these compounds and facilitates excretion in bile.

In addition to forming OH-PCBs, arene oxide intermediates can undergo further metabolism to form methyl sulfone PCBs (MeSO2-PCBs) which can accumulate in adipose or specific tissue. Both MeSO2-PCBs and OH-PCBs can accumulate in specific tissue such as the lung and fetus. The flow chart below summarizes the biological fate of typical PCBs within the human body.


from the Handbook of Environmental Chemistry vol 3. part K, 2000 33

Excretion of PCB’s is dependent on the rate of metabolism to polar products. Most PCB congeners display biphasic elimination; The initial half life is short, but the later half life is long and structure dependent. The rate of metabolism for each congener depends on the number and position of chlorine atoms. As stated, highly chlorinated PCBs with para-chlorines remain in the body longer than less chlorinated congeners with chlorine-unsubstituted meta-para-carbons. Metabolites of all congeners are eliminated primarily through bile and fecies. However, a small degree of elimination (<5%) can occur through urine for less chlorinated congeners.

REFERENCES:

New Types of Persistent Halogenated Compounds (Ed. by J. Paasivirta). The Handbook of Environmental Chemistry Vol 3. Part K. Springer-Verlag, Berlin Heidelberg. 2000

Wolf MS. 1985. Occupational Exposure to Polychlorinated Byphenyls (PCBs). Environmental Health Perspective 60: 133-138.

Schlummer M, Moser GA, McLachlan MS. 1998. Digestive tract absorption of PCDD/Fs, PCBs, and HCB in humans: Mass balances and mechanistic considerations. Toxicol Appl Parmacol 152: 128-137.


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