Toxicology

PCBs have a relatively low acute toxicity to vertebrates, and highly variable toxicity to other organisms. PCB congeners show different modes of toxic action, and have been shown to have a wide range of chronic toxic effects, including carcinogenicity, and effects on the immune, reproductive, endocrine, and nervous systems. Although the toxicology of PCBs has been studied more than many other organic pollutants, there are still many aspects that are not well understood.

The bioconcentration and bioaccumulation of PCBs leads to the increased likelihood of toxic effects being expressed with increasing trophic level, and many of the most toxic PCB congeners are particularly persistent and bioaccumulative. Top predators are, therefore, most likely to accumulate concentrations of PCBs which lead to toxic effects, and predatory birds and mammals in the Northern Hemisphere are particularly susceptible because oftheir high food intake requirements (compared to cold-blooded predators) and the fact that they live in the regions where PCBs were predominantly used. Marine top predators are most at risk because of the high degree of bioconcentration in the lower trophic levels of the marine ecosystem, the presence of high levels of body fat in warm-blooded aquatic organisms, and because many marine predators have particularly strong seasonal fasts (e.g., hibernation in polar bears, fasting during lactation and moulting in seals).

After acute exposure of mammals and birds to commercial mixtures, documented toxic effects include weight loss, behavioral changes, alopecia, acne, facial oedema, diarrhea, anemia, reduced fecundity, and high mortality of adults and offspring. However, it should be noted that some of the toxic effects seen may be due to the action of impurities in the PCB commercial mixtures, especially of 'dioxins' (polychlorinated dibenzo-/>-dioxins and dibenzofurans) which are often produced during the production of PCBs, and can also be produced during certain uses in which high temperatures are encountered.

The effects of chronic PCB exposure which have been documented in vertebrates include

• reproductive effects, including reduced conception and live birth rates, reduced birth weights, and reduced sperm counts;

• neurological effects, including reduced neurological development (including on eyesight and memory);

• effects on the endocrine system, including decreased thyroid hormone levels;

• immune system effects, including decreased size of the thymus, reduced immune system response, and reduced resistance to viral and other infectious agents;

• cancer, particularly of the liver.

Many of the toxic effects of PCBs do not have a 'no observable effect dose', meaning that there is no safe minimum dose below which the effect does not cause an increase in the likelihood of the effect occurring.

Some of the toxic effects of PCBs are likely to be primarily, or partly, caused by the hydroxymetabolites of PCBs, and possibly the short-lived reactive intermediates produced during metabolism.

Determining the toxic effects of PCBs is complicated by two very important factors:

1. PCBs were used as a large number of complex commercial mixtures, which often contain potentially toxic impurities - different PCB congeners have different effects, which are difficult to identify separately when investigating using a mixture, and are also difficult to identify separately from the effects of different impurities

2. In the environment, biota are exposed to a wide range of chemicals, of both natural and anthropogenic origins, which have potential toxic effects - the effects of PCBs are usually very difficult to separate from the effects of these other chemicals, and indeed, the effects of different chemicals may 'interfere' with each other; interactions may be synergistic, or antagonistic, rather than being simply additive.

The toxicity of PCBs has been tested under a range of conditions using both commercial mixtures (often with specific impurities, such as polychlorinated dibenzo-p-dioxins and dibenzofurans, removed) and individual PCB congeners, which has allowed the toxic effects of different classes of PCB congeners to be differentiated and described. This is dealt with in more detail below. However, although PCBs have been implicated in certain toxic effects in the field, the actual impact of PCBs on field observations of toxic effects has not been satisfactorily quantified as there is insufficient data and knowledge about the effects of the chemical mixtures present for firm epidemiological conclusions to be drawn. For example, there is evidence that PCBs are immune suppressants in mammals (from controlled studies, e.g., in one study seals were fed fish containing high concentrations of PCBs), but a number of field studies of seals have been unable to separate potential immune-suppressant effects of PCBs from other persistent pollutants, such as organochlorine pesticides, which are often also present at relatively high concentrations, and were controlled and regulated at similar times leading to similar temporal changes in concentrations.

Toxic modes of action for coplanar PCBs

PCBs that do not possess chlorine atoms substituted at the ortho positions are called 'coplanar' congeners, as they can take a planar molecular shape. These congeners can bind to the cytosolic aryl hydrocarbon receptor (Ah receptor), and exhibit toxic effects similar to 2,3,7,8-tetrachlorodi-benzo-p-dioxin (the most toxic of the 'dioxins' -polychlorinated dibenzo-p-dioxins and dibenzofurans). This form of toxicity is often manifest as hepatotoxicity, embryo mortality, and induction of CYP1A1 and CYP1A2. Induction of the CYP enzymes can lead to synergistic effects between PCBs and other chemicals, as the activation of some mutagens and carcinogens may become enhanced, leading to increased DNA adduct formation. Some hydroxymetabolites of coplanar PCBs are structurally similar to thyroxine (T4), and can compete with T4 for binding sites on transthyretin, with associated physiological effects.

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin is also expressed to different degrees for a number of different polychlorinated dibenzo-p-dioxins and dibenzofurans, and coplanar PCBs (i.e., each has a different level of toxicity relative to dose). However, the total 'dioxin-like' toxicity of a mixture has been found to be simply (or predominantly) additive, and is directly related to the sum of the dose of each of the chemicals with dioxin-like toxicity multiplied by a factor to correct for the relative toxicity of each component. The correction factor for each chemical component in this calculation is derived from in vitro and in vivo tests, and is called a toxic equivalence factor (TEF). The TEF multiplied by a dose or concentration gives the 'toxic equivalent' (TEQ) - the dioxin-like toxicity from that chemical, expressed as an equivalent dose or concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin, in the same units. It has been found that, in environmental samples, the total dioxin-like toxicity from PCBs can actually exceed that of PCDD/Fs themselves. The current TEF values for 'dioxin-like' PCBs in fish, birds, and mammals (including humans), assigned by the World Health Organization in 1997, and reassigned for mammals in 2005, are shown in Table 2. It can be seen that there are marked differences

Table 2 TEF values for PCBs, assigned by the WHO in 1997 and 2005

PCB name

number

WHO 1997 TEF fisha

WHO 1997 TEF birdsa

WHO 2005 TEF humans and mammalsb

3,3',4,4'-tetrachlorobiphenylc

PCB 77

0.0001

0.05

0.0001

3,4,4',5-tetrachtarobiphenylc

PCB 81

0.0005

0.1

0.0003

3,3',4,4',5-pentachtarobiphenylc

PCB 126

0.005

0.1

0.1

3,3',4,4',5,5'-hexachlorobiphenylc

PCB 169

0.00005

0.001

0.03

2,3,3',4,4'-pentachlorobiphenyld

PCB 105

<0.000005

0.0001

0.00003

2,3,4,4',5-pentachtarobiphenyld

PCB 114

<0.000005

0.0001

0.00003

2,3',4,4',5-pentachlorobiphenyld

PCB 118

<0.000005

0.00001

0.00003

2,3',4,4',5'-pentachlorobiphenyld

PCB 123

<0.000005

0.00001

0.00003

2,3,3',4,4',5-hexachlorobiphenyld

PCB 156

<0.000005

0.0001

0.00003

2,3,3',4,4',5-hexachlorobiphenyld

PCB 157

<0.000005

0.0001

0.00003

2,3',4,4',5,5'-hexachlorobiphenyld

PCB 167

<0.000005

0.00001

0.00003

2,3,3',4,4',5,5'-heptachlorobiphenyld

PCB 189

<0.000005

0.00001

0.00003

aAdapted from van den Berg M, Birnbaum L, Bosveld ATC, et al. (1998) Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspectives 106: 775-792.

bAdapted from van den Berg M, Birnbaum LS, Denison M, et al. (2006) The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicological Sciences 93: 223-241. cNon-ortho substituted. dMono-ortho substituted.

aAdapted from van den Berg M, Birnbaum L, Bosveld ATC, et al. (1998) Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspectives 106: 775-792.

bAdapted from van den Berg M, Birnbaum LS, Denison M, et al. (2006) The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicological Sciences 93: 223-241. cNon-ortho substituted. dMono-ortho substituted.

in the relative toxicities of PCBs to fish, birds, and mammals. It should be noted that TEF values are intended for estimating dioxin-like toxicity from oral ingestion only.

Toxic modes of action for noncoplanar PCBs

Although the dioxin-like toxicity of coplanar PCBs has received a great deal of attention, it has become apparent that the noncoplanar PCBs also have a range of toxic effects. It is notable that, in commercial mixtures and the environment, the coplanar PCBs are present at much lower concentrations than many of the noncoplanar PCBs, so even noncoplanar PCBs with relatively low toxicity may have appreciable effects at the doses received compared to coplanar PCBs. Some of the toxic effects of noncoplanar PCBs are the same as, or similar to, the non-dioxin-like toxic effects of coplanar PCBs.

Toxic effects of orZ^o-substituted PCBs that have been documented include neurotoxicity (e.g., decreased cate-cholamine levels in the brain and behavioral changes), effects on insulin production, and effects on the endocrine system (e.g., oestrogen-like activity of PCBs and their metabolites). The mechanisms leading to these effects are not well understood, but are likely to be related (at least partly) to hydroxy-metabolites, and include interference in signal transduction pathways and intracellular Ca2+ homeostasis (for neurological problems), and the rigidity of noncoplanar PCBs (and metabolites) allowing action on steroid and hormone receptors.

It is important to note that the toxic effects of non-coplanar PCBs are not dioxin-like, and are not encompassed at all in the use of TEFs described above. Similar effects may be seen from exposure to a range of biogenic and anthropogenic chemicals present in the environment, and, as such, the mixture toxicity effects of additivity, synergy (enhancement), and antagonism (reduction) may be seen. Because of this, and the relatively low concentrations of PCBs generally present in the environment, it is also extremely difficult to quantify the effects of PCBs separately from other chemicals, and even large-scale (extremely expensive) epidemiological studies in the field may not elucidate the impact of each component separately.

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