PCBs and Our Sense of Smell

PCBs may damage our sense of smell. Olfactory changes occur with PCB exposure.

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PCBs and Our Sense of Smell

Studies indicate that PCB exposure in the womb, even just one PCB dose on one critical day in the pregnancy, could cause changes in a child’s sense of smell, through changes in the olfactory parts of the brain. Additional studies show that PCBs accumulate in adults selectively in the nasal passages and olfactory organs, and alter the local chemistry, which may affect an adult’s sense of smell.
This area of research seems neglected in humans, perhaps because a partly-impaired sense of smell may not be obvious or as high a priority as learning disabilities or other effects.
Sense of Smell, Sensory Perception

Study #1

altered neurotypic protein, glial protein, and serotonin in the lateral olfactory tract (brain’s center of smell)

study used offspring of female rats fed PCBs

The underlying mechanisms of PCB-induced developmental neurotoxicity are unclear, although it is a plausible hypothesis that pre- or postnatal PCB exposure indirectly affects brain development by transiently reducing the amount of thyroid hormone in the brain. We therefore examined the effects of pre- and postnatal PCB exposure on thyroid hormone levels in the plasma and brain of developing rats, the mechanisms involved in altered thyroid hormone homeostasis and which brain regions and cell types were affected. The results indicate that when pregnant rats are exposed to Aroclor 1254, there is a substantial accumulation of the hydroxylated PCB metabolite, 2,4,5,3',4'-pentachloro-4-biphenylol (4-OH-pentaCB) in the fetal plasma and brain. The accumulation of 4-OH-pentaCB in the plasma is probably responsible for the dramatic reductions in plasma and brain T4 concentrations by blocking the transport of thyroid hormone to the fetus. However, the fetal brain may be able to compensate for the decreases in T4, by increasing the conversion of T4 to T3. Despite the lack of an observed effect of maternal PCB exposure on brain T3 levels in the offspring, the levels of a neurotypic protein (synaptophysin) and a glial protein (glial fibrillary acidic protein, GFAP) as well as serotonin metabolism were altered in the brain of adult offspring in a complex fashion. The most prominent neurochemical alterations were found in the lateral olfactory tract, prefrontal cortex and the brainstem. The neurochemical data could be interpreted as the result of a primary lesion in the brainstem early in development. (Morse et al, 1995)

Study #2

increased serotonin in lateral olfactory tract
study used offspring of female rats fed PCBs

Pregnant Wistar WU rats were administered PCBs (0, 5 or 25 mg Aroclor 1254 per kg body weight) by gavage on day 10 to 16 of gestation. Levels of biogenic amines were measured in the lateral olfactory tract, prefrontal cortex, striatum, hippocampus and hypothalamus in male and female offspring 21 and 90 days after birth. 5-Hydroxyindole acetic acid (5-HIAA) concentrations and the ratio of 5-HIAA/5-hydroxytryptamine (5-HT, serotonin) were significantly increased in the lateral olfactory tract, prefrontal cortex and hippocampus on postnatal day 90 in male and female offspring following maternal PCB treatment. No effects were observed on regional brain levels of dopamine, 3,4-dihydroxyphenylacetic acid, norepinephrine and homovanillic acid. The results indicate that pre- and postnatal exposure to Aroclor 1254 results in regionally specific long-term alterations in the serotonergic system. (Morse et al, 1996)

Study #3

increased glial fibrillary acidic protein (GFAP) in the lateral olfactory tract
reduced synapatophysin levels (a neurotypic protein) in the lateral olfactory tract
study used offspring of female rats fed PCBs

Pregnant Wistar WU rats were exposed to 0, 5, and 25 mg of the commercial polychlorinated biphenyl (PCB) mixture Aroclor 1254 per kilogram of body weight on Days 10 to 16 of gestation. Pregnant rats were sacrificed on Gestation Day 20 to observe effects on fetal body and brain weights. Male and female offspring were sacrificed on Postnatal Days 21 and 90 (PND21 and PND90, respectively) and examined for treatment-related effects on neurochemical parameters. The concentrations of the neuronal and glial cell markers, synaptophysin and glial fibrillary acidic protein (GFAP), were measured in diverse brain regions from the offspring using immunochemical techniques. The level of calcineurin (a calmodulin-regulated protein phosphatase) activity was measured in cerebellar homogenates. In addition, ethoxyresorufin O-deethylase (EROD) activity was determined in hepatic microsomes as a measure of a well-characterized response to PCB exposure in experimental animals. The major alterations of GFAP levels following maternal PCB treatment were significant increases in the lateral olfactory tract and the cerebellum (CB) and significant decreases in the brain stem (BS) of the offspring on PND21 and 90. Synaptophysin levels were significantly decreased relative to controls in the lateral olfactory tract, prefrontal cortex, and striatum of the offspring on PND90. In the BS, synaptophysin levels were significantly decreased relative to controls in male and female weanlings on PND21 and males on PND90; however, significant increases were observed in the BS of females on PND90. No effect of maternal PCB treatment was observed on levels of GFAP and synaptophysin in the dorsal hippocampus on PND21 and 90. Due to analytical restrictions statistical comparisons of GFAP levels were limited to examining the effect of maternal PCB treatment per brain region per sex per time point. Calcineurin activity was decreased in the female CB on PND21, but a significant increase in activity was observed in the female CB on PND90. No effect of maternal PCB treatment was observed on the cerebellar calcineurin activity in male offspring on PND21 and 90. EROD activity was highly induced in maternal microsomes from both PCB treatment groups, but only slightly induced in fetal hepatic microsomes. On PND21 weanling hepatic microsomal EROD activity was highly induced following gestational and lactational PCB exposure; however, on PND90 EROD activity was unaffected by maternal PCB treatment in male offspring and significantly decreased in female offspring. The results of the present study indicate that gestational and lactational exposure to the commercial PCB mixture results in long-term alterations in a neuronal and glial cell markers in specific brain regions of rats. These marker proteins may be useful for determining the structure-activity relationships in PCB-induced developmental neurotoxicity. (Morse et al, 1996)

Study #4

PCBs changed the structure of olfactory bulbs
study used eagles (deformed, therefore probably exposed to PCBs through mother’s PCB exposure)

Observations of several avian species (heron, cormorant, chicken) indicates that in ovo exposure to PCBs and/or PCDDs throughout embryogenesis is correlated with the development of a gross brain asymmetry which is detectable in the young hatchlings. This asymmetry is readily quantifiable by taking external measurements on whole, fixed brain. However, under certain circumstances one may not or cannot sacrifice animals which are likely to have been exposed to these compounds, and therefore may have asymmetric brains. We report here that under circumstances when it is desirable or necessary to detect a gross brain asymmetry without sacrificing the animal, it is possible to use non-invasive computer tomographic (CT) scanning technology. CT scans were taken of the brains of four eagles with PCB-related external deformities as well as one "reference" eagle. Measurements of the CT scans are compared to gross external measurements made on the intact fixed brains. These measurements indicate that the gross asymmetry is detectable in both external measurements as well as in the CT scans. Major brain regions that appear to be affected include the forebrain, tecta and the olfactory bulbs. (Henshel et al, 2000)

Study #5

low level air exposure to PCBs
PCBs accumulate selectively in olfactory bulbs
the congener mix of PCBs in the olfactory bulbs resemble the mix found in the air
PCBs may enter nose and directly travel to the olfactory bulbs
study used adult ferrets

Ferrets, mammalian carnivores, kept in an indoor enclosure were continuously exposed to low concentrations of polychlorinated biphenyls (PCBs) in the ambient air for 5 years. After that time PCB concentrations were quantified in the olfactory bulbs and in the remaining brain, adipose tissue and liver. The results revealed unexpectedly high PCB concentrations in the olfactory bulbs, surpassing those in the remaining brain and the peripheral tissues. The PCB congener pattern in the olfactory bulbs resembled that found in the ambient air and the less chlorinated volatile PCBs were found in higher concentrations. We, therefore, assume that airborne PCBs enter directly via the olfactory system and are transported through the axons to the olfactory bulbs where they accumulate. (Apfelbach et al, 1998)

Study #6

injected PCBs tend to concentrate selectively in the olfactory region
study compares enzyme activity at various sites
study used adult rats

Recent studies on several enzymes of the respiratory tract that participate in bioactivation and detoxication of xenobiotics and hydroxylation of benzo(a)pyrene (50328) (BP) were summarized. Antibodies to metabolizing enzymes were raised after purification of enzymes from rat liver. Enzymes were located within rat pulmonary tissues by immunoperoxidase and immunofluorescent staining. Major isozymes of hepatic microsomal cytochrome-P450 and glutathione-S-transferases, and also epoxide-hydrolase, were found in olfactory and respiratory epithelial cells and cells of Bowman's and seromucous glands. There were differences in staining intensities of most antigens within nasal mucosa cells. Histochemical study of intranasal localization of aryl-hydrocarbon-hydroxylase activity showed that BP underwent hydroxylation within olfactory and respiratory epithelia and Bowman's and seromucous glands. The olfactory region of the nasal mucosa had significantly greater monooxygenase activity than did the respiratory region. Preincubation with antibodies against cytochrome-P450-reductase caused pronounced inhibition of benzo(a)pyrene-hydroxylase (BPOHase) activity, especially in the olfactory region, confirming immunohistochemical findings. Seven days after administration of intraperitoneal Aroclor-1254, staining for cytochrome-P450-BNF-B and cytochrome-P450-MC-B increased dramatically, with the olfactory region still containing greater concentrations than the respiratory region. The most pronounced increase in BPOHase activity was in the respiratory region. In lung, Aroclor-1254 induced cytochrome-P450 isozymes in a limited number of cells. Hydroxylase activity was enhanced throughout epithelia. The results suggested that other cytochrome-P450 isozymes capable of hydroxylating BP but immunochemically unrelated to hepatic microsomal cytochromes were induced by Aroclor-1254. The authors conclude that xenobiotics can be bioactivated and detoxified at numerous sites within the respiratory tract, but that xenobiotic metabolizing enzymes and BPOHase activity may not be distributed uniformly within individual segments of the tract. (Baron et al, 1988)

Study #7

PCBs and furans accumulate in the nasal olfactory mucosa (nasal passages)
study used offspring of female rats fed PCBs

The effects of polychlorinated biphenyls (PCBs) on tissue accumulation of 2,3,7,8-tetrachlorodibenzofuran (51207319) (TCDF) were studied in mice. Pregnant and nonpregnant female NMRI-mice were pretreated intraperitoneally with 25 to 100mg/kg 3,3',4,4'-tetrachlorobiphenyl (32598133) (I-77), 2,3',4,4',5-pentachlorobiphenyl (I-118), 3,3',4,4',5-pentachlorobiphenyl (I-126), 2,3,3',4,4'-pentachlorobiphenyl (I-105), 2,3,3',4,4',5-hexachlorobiphenyl (I-156), 2,2',4,4',5,5'-hexachlorobiphenyl (35065271) (I-153), 3,3',4,4',5,5'-hexachlorobiphenyl (32774166) (I-169), or aroclor-1254 (11097691) 4 or 48 hours before they were injected intravenously with 40 or 800 micrograms per kilogram (microg/kg) tritium (H3) labeled TCDF on days ten, 14, 16, or 17 of gestation. The nonpregnant mice were killed 7 or 28 days after TCDF. The pregnant mice were killed on gestational day 17. The livers were removed. Hepatic uptake of TCDF was determined by autoradiography. The extrahepatic tissue distribution of TCDF derived radioactivity was determined. Significant amounts of TCDF accumulated in the livers of all mice. Significant accumulations of TCDF derived radioactivity were also detected in the bladder and nasal olfactory mucosa 7 days after dosing in nonpregnant mice and in pregnant mice. In pregnant mice, small amounts of H3 activity were seen in the fetal liver and intestines following 40microg/kg TCDF, most notably 1 day after exposure. Following 800microg/kg TCDF, large amounts of radioactivity were seen in the fetal liver and nasal passages. I-156, I-153, and aroclor given 4 hours before TCDF significantly increased hepatic uptake of H3 activity. Pretreatment with I-126 and I-77 significantly decreased hepatic uptake of radioactivity. The other PCBs did not significantly affect hepatic uptake of H3 activity. When given 48 hours before TCDF, I-105, I-156, and I-169 significantly increased hepatic uptake of H3 activity. I-77, I-105, I-118, I-153, and I-169 slightly, nonsignificantly decreased TCDF uptake by the lungs. The authors conclude that TCDF accumulates in the liver and nasal olfactory mucosa of dams and fetal mice. Nonortho substituted PCBs decrease hepatic uptake of TCDF and ortho substituted PCBs increase hepatic TCDF uptake. (Darnerud et al, 1993)

Study #8

PCBs increased anti-cytochromo P450- binding in olfactory epithelia
study used adult rats

Cytochrome P450 1A1 was localized immunohistochemically and benzo[a]pyrene hydroxylase activity was identified in situ by means of fluorescence histochemistry in the nasal mucosa of untreated, 3-methylcholanthrene-treated or Aroclor 1254-treated rats. Cytochrome P450 1A1 was localized predominantly within Bowman's glands, with considerably less staining occurring in the olfactory epithelium of untreated rats. Similarly, benzo[a]pyrene was hydroxylated to the greatest extent in Bowman's glands and, to a lesser extent, in olfactory epithelial cells. Pre-treatment of tissue sections of nasal mucosa with anti-P450 1A1 inhibited most of the benzo[a]pyrene hydroxylase activity present. Although 3-methylcholanthrene treatment did not affect either cytochrome P450 1A1 or hydroxylase activity in the nasal mucosa, a single intraperitoneal injection of Aroclor 1254 significantly increased anti-P450 1A1 binding in Bowman's glands and in the olfactory and respiratory epithelia, and dramatically enhanced benzo[a]p (--- citation incomplete) (Voigt et al, 1991)

Study #9

PCBs decreased dopamine concentrations
PCBs decreased dopamine metabolite concentrations in the lateral olfactory tract
study used adult male rats

A series of subchronic feeding experiments were undertaken employing powdered rat chow adulterated with either 500 or 1000 parts per million (ppm) Aroclor-1254 (11097691) in order to determine what changes occurred in male Wistar-rats as a result of such treatment. Following a 30 day exposure the animals were sacrificed. Polychlorinated biphenyl (PCB) exposure slowed the normal increase in weight gain but there was no statistical relationship between the change in body weight and neurochemical change. PCB exposure caused a significant decrease in striatal dopamine (DA) concentrations. The major metabolites of DA, homovanillic-acid (HVA) and 3,4-dihydroxyphenylacetic-acid (DOPAC), also decreased significantly following exposure. Neuronal turnover was also changed. The DOPAC ratios were significantly decreased. HVA/DA ratios were also affected by exposure. No statistically significant changes in striatal concentrations or activity of norepinephrine or serotonin were noted. In the lateral olfactory tract (LOT), Aroclor-1254 exposure did not cause statistically significant decreases in DA concentration, but there were dose dependent decreases in metabolite concentrations. No differences in biogenic amine function other than for DA were noted in the LOT. Chow contaminated with acetone (67641) showed no differences from those treated only with the PCB. In the 1000ppm treatment group, total PCB concentrations in the hippocampus, striatum and LOT were 52.6, 41.6, and 30.4 micrograms/gram wet weight, respectively, while in the 500ppm group the total PCB concentrations were 29.6, 16.2, and 14.3 micrograms/gram wet weight, respectively. (Seegal et al, 1991)

Study #10

PCBs reduced the DOPAC/domamine ratio in the olfactory tract
study used adult male rats

The effects of exposure to polychlorinated biphenyls on dopamine (51616) metabolism were studied in adult male Wistar-rats. The polychlorinated biphenyl mixture consisted of equal weights of Aroclor-1254 (11097691) and Aroclor-1260 (11096825) in corn oil. Animals received a single oral dose of the mixture at 0.5 milliliter per 100 grams body weight, resulting in a final dose of either 500 or 1,000 milligrams of polychlorinated biphenyls per kilogram body weight. Animals were sacrificed 1, 3, 7, or 14 days after treatment, and brains were rapidly removed to determine concentrations of dopamine and its major metabolites, 3,4-dihydroxyphenylacetic-acid (DOPAC) and homovanillic-acid (HVA) by high performance liquid chromatography with electrochemical detection. Dopamine and DOPAC concentrations in caudate decreased after exposure to polychlorinated biphenyls, as did HVA/dopamine ratios. Dopamine concentrations in the olfactory tract were unaffected, although DOPAC/dopamine ratios decreased. The authors conclude that the mature mammalian nervous system is sensitive to a brief exposure to polychlorinated biphenyls and that regional differences exist in the neurochemical sequelae of exposure to polychlorinated biphenyls. (Seegal et al, 1986)

News Article

The following article appeared in the Gazette Reporter, a New York newspaper: "State studies nerves and PCBs --- Scope of health study expanded." By Judy Patrick, Gazette Reporter.

HUDSON FALLS, NY - The state Health Department is expanding the scope of a research project on the potential neurological effects of PCB exposure.The study focuses on long-time residents of the Washington County villages of Hudson Falls and Fort Edward to see if there is any connection between PCB exposure and biological changes in the nervous system.

Results of an initial pilot study, involving 39 people, indicated a need to increase the size of the study from 100 to 200 people, as well as to look at the incidence of other substances, particularly mercury and pesticides, in the blood in addition to PCBs."The study has been very well publicized and we've gotten some input from the community. We have, as a result, made some changes," said Claire Popsipil, a Health Department spokeswoman. In general, she added, the more people in the study the better in terms of accuracy.

The goal of the study is to determine if PCBs can cause biological changes in the nervous system.The two villages were chosen because they are places where PCBs were used in manufacturing. PCB-laden discharges into the Hudson River from a General Electric Co. plant in Hudson Falls have been blamed for that river's heavy concentration of PCB pollution.While the Health Department has undertaken a number of other PCB-related research projects in the past, this is the first that looks on potential neurological impacts of PCB exposure, she said.

"Studies have suggested that the nervous system is more sensitive to PCBs, and the effects may be evident at lower levels of exposure," Popsipil said.To be included in the study, people must be 55-74 years old and have lived in the area for at least 25 years. For comparison purposes, the study also includes a control group of people from Glens Falls - upriver from where PCBs were used in manufacturing."The reason we're picking people of that age is that older people have greater cumulative and peak exposure to PCBs as opposed to someone younger," she said.

The project focus is on past and current PCB exposure either via airborne PCBs or by consuming fish from the Hudson River, not directly from working in a manufacturing process involving PCBs. The study takes note, for example, of where participants live in relationship to the Hudson River and to factories where PCBs were used.In addition to measuring the level of PCBs in the blood of participants, the study will also test the air inside and outside their homes to see if it contains PCBs.

The nervous system tests will measure changes in short-term memory, muscular movement and sense of smell.The Hudson River PCB research project is just the latest in a string of PCB-related studies the Health Department has undertaken in recent years, from studying Transportation Department workers exposed to PCB-laden sediment while dredging the Hudson River to improve navigation to firefighters exposed to PCBs while fighting a transformer fire at a Binghamton office building. "PCB-related research is ongoing," she said.There has been, for example, an early 1990s study of cancer incidence and birth defects among residents of Waterford, who use the Hudson River as their source of drinking water. That study found no higher than normal incidence of cancer or birth defects, she said.

The federal Agency for Toxic Substance Disease Registry, part of the Centers for Disease Control, is paying the $600,000 cost of the three-year upper Hudson River study. Dr. Edward Fitzgerald of the Health Department's Center for Environmental Health in Troy is overseeing the research, due to be complete by the end of 2002.

Sense of Smell, Olfactory Gland

Links to More Information

The Society for Neuroscience --- includes an excellent diagram and description of the process of smelling.

HYPOHH is a patient support organisation for sufferers of a specific group of rare hormonal diseases called hypogonadotrophic hypogonadism. Their webpage includes detailed information about how we develop our sense of smell, under the heading "Kallman’s syndrome." This syndrome is a rare disorder which affects predominantly men. Typical characteristics are a failure to go through puberty and an absent sense of smell.

References

Apfelbach R, Engelhart A, Behnisch P, Hagenmaier H The olfactory system as a portal of entry for airborne polychlorinated biphenyls (PCBs) to the brain? [letter] Arch Toxicol; VOL 72, ISS 5, 1998, P314-7

Baron J, Burke JP, Guengerich FP, Jakoby WB, Voigt JM Sites for Xenobiotic Activation and Detoxication within the Respiratory Tract: Implications for Chemically Induced Toxicity. Toxicology and Applied Pharmacology, Vol. 93, No. 3, pages 493-505, 68 references,1988

Darnerud PO, Tornwall U, Bergman A, Brandt I Liver Accumulation of 2,3,7,8-Tetrachloro-(3H)dibenzofuran in Mice: Modulation by Treatments with Polychlorinated Biphenyls. Chemico-Biological Interactions, Vol. 89, Nos. 2/3, pages 89-102, 31 references, 1993

Henshel DS, Martin JW, Nelson C, Rosenfield D, Sikarski J, Bolander R, Bowerman W, Best D Using computer tomography to detect gross brain asymmetry induced by exposure to environmental pollutants. Neurotoxicology 2000 Feb-Apr;21(1-2):257 Author Address: School of Public and Environmental Affairs, Indiana University, Bloomington, IN.

Morse DC, Brouwer A, van den Berg KJ, Seegal RF Prenatal exposure to polychlorobiphenyls: PCB metabolism, thyroid hormone homeostasis and brain development in the rat. Neurotoxicology 1995 Fall;16(3):535 Author Address: Department of Toxicology, Agricultural University, Wageningen, The Netherlands.

Morse DC, Seegal RF, Borsch KO, Brouwer A Long-term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat. Neurotoxicology 1996 Fall-Winter;17(3-4):631-8 Author Address: Department of Toxicology, Wageningen Agricultural University, The Netherlands.

Morse DC, Plug A, Wesseling W, van den Berg KJ, Brouwer A Persistent alterations in regional brain glial fibrillary acidic protein and synaptophysin levels following pre- and postnatal polychlorinated biphenyl exposure. Toxicol Appl Pharmacol 1996 Aug;139(2):252-61 Author Address: Department of Toxicology, Agricultural University, Wageningen, The Netherlands. dcmorse@eohsi.rutgers.edu

Seegal RF, Brosch KO, Bush B Polychlorinated Biphenyls Produce Regional Alterations Of Dopamine Metabolism In Rat Brain. Toxicology Letters, Vol. 30, No. 2, pages 197-202, 21 references, 1986

Seegal RF, Bush B, Brosch KO Sub-chronic Exposure of the Adult Rat to Aroclor 1254 Yields Regionally-Specific Changes in Central Dopaminergic Function. Neurotoxicology, Vol. 12, No. 1, pages 55-65, 54 references, 1991

Voigt JM, Guengerich FP, Baron J. Localization and induction of cytochrome P450 1A1 and aryl hydrocarbon hydroxylase activity in rat nasal mucosa. J Histochem Cytochem; VOL 41, ISS 6, 1993, P877-85 Author Address: Department of Pharmacology, University of Iowa, Iowa City.