15. Case study on Dioxins/Furans in Japan

SHINGO KIMURA

Office of Environmental Risk Assessment

Environment Agency of Japan

 

The Report of AD HOC COMMITTEE ON DIOXIN RISK ASSESSMENT (Summary)

This report was issued in May 1997 as the report of "AD HOC Committee on Dioxin Risk Assessment". This Committee is an advisory body for Director of Environmental Health Department, Japan's Environment Agency.

 

Part 1: Physical / Chemical Properties of Dioxins

 

Dioxin is the general name of a group of chemical substances, including polychlorinated dibenzo-p dioxins (PCDD) and polychlorinated dibenzofurans (PCDF), which are the unintentional by-products from combustion, incineration or chemical manufacturing /processing. PCDD and PCDF consist of 75 and 135 congeners, respectively.

 

Part 2: Health Effect Assessment 

The main routes of absorption of dioxins are the digestive tract, skin, and lung. Regardless of the route, the rate of absorption differs depending on the animal species, vehicle, isomer of dioxin, other substances present in diet, dosage, and animal age. In general, the rate of absorption decreases as the dose is increased and as the number of chlorine atoms in the dioxin is increased.

Ingested dioxins enter the bloodstream and are distributed to all tissues of the body. Depending on the isomer of dioxin, the dioxins tend to accumulate, mainly in the liver and adipose tissue. Human and laboratory animals have different characteristics as to which of these tissues stores more dioxin. In humans, more is stored in adipose tissue, while in laboratory animals, excluding guinea-pigs, more is stored in the liver.

In general, dioxins are resistant to metabolize. Several metabolites excreted into bile were identified, and less toxic than that of the parent dioxins.

Large differences in rate of excretion of dioxins were also observed between humans and laboratory animals. For example, the half-life of 2,3,7,8- tetrachlorodibenzodioxin (2,3,7,8-TCDD) in humans is more than 100 times longer than that in rats. The half-life of 2,3,7,8-TCDD in monkeys is somewhere in between that in humans and those in other laboratory animals. Aside from monkeys, laboratory animals show similar excretion rates.

Dioxins, through Ah receptors (1), induce enzymes such as CYP1A1, CYP1A2, cytochrome P-45O(2) dependent monooxygenases. CYP1A2, in particular, tends to bind to dioxins. The mechanisms of these processes involving enzymes and dioxins are closely related to accumulation of dioxin in the liver and the mechanisms of toxicity. Factors determining the transport of 2,3,7,8-TCDD through the living body are its solubility and diffusion in adipose tissue, binding with CYPlA2 in the liver, excretion, and biotransformation. 

2. General Effects

Acute toxicity test revealed extremely wide interspecies differences in lethal toxicity. Most susceptible were guinea-pigs (males), whose LD5O was 600 ng/kg, while the least susceptible were hamsters (male) at 5,000,000 ng/kg. Females appears more susceptible to dioxins than males.

From results of subchronic toxicity tests, no observed adverse effect level (NOAEL) in rats, mice and guinea-pigs was estimated to be 10 ng/kg/day, 100 ng/kg/day, and 0.6 ng/kg/day, respectively.

Swiss strain mice given 2,3,7,8-TCDD orally for one year were found to manifest amyloidosis and dermatitis, with a lowest observed adverse effect level (LOAEL) of 1 ng/kg/day. B6C3F1 mice were given oral doses for two years, with the results showing NOAEL of 1.4 ng/kg/day for males and 6 ng/kg/day for females.

Episodes of human exposure to dioxins were reported to be sewage from factories which polluted the environment in the United States or accidents in factories or laboratories, case in Seveso, Italy, and veterans who were involved in herbicide scattering operation in the Vietnam War.

Symptoms and conditions observed in animals and people exposed to 2,3,7,8-TCDD include weight loss (wasting syndrome), atrophy of the thymus, obstructed hepatic metabolism, cardiac muscle damage, changes in metabolism of sexual hormones, thyroid hormones, and cholesterol and other fatty substances, dermic symptoms such as chloracne, and symptoms related to central nervous system damage, such as reduced ability to study.

3. Carcinogenicity

In long-term tests using laboratory animals, 2,3,7,8-TCDD and related substances were found carcinogenic in rats, mice, hamsters, and other animals. Kociba and coworkers (1978) found a significant increase in hyperplastic nodules and the occurrence of carcinomas in the liver of female rats and identified squamous cell carcinomas of the nasal turbinates/hard palate in two male rats, squamous cell carcinomas of the tongue in a male rat, lung tumor in female rats. NTP (1982) reported an increase in hyperpiastic nodule in the liver of female rats and thyroid gland follicular tumors in male rats. The NOAEL values reported are 1 ng/kg/day and 1.4 ng/kg/day, respectively.

Dioxins have been recognized as cancer promoters in the two-step model of carcinogenesis in the liver, lung and skin of the rat and mouse. It is speculated that the promotion in development of liver cancer is implicated in a loss of epidermal growth factor and/or the role of estrogen.

2,3,7,8-TCDD was recognized to indirectly cause damage to DNA, but no direct effect such as production of TCDD-related DNA adducts has been observed. A battery of mutagenicity tests was found negative in most cases and it was concluded that 2,3,7,8-TCDD does not have genotoxicity.

Regarding epidemiological data on dioxins, all kinds of oncological investigations have been performed on occupational exposures, accidental exposure, and exposure of veterans of the Vietnam War who were involved in Ranch Hand operation. Taken together with the above-mentioned results, it is suggested that there is a "threshold" for development of cancer caused by 2,3,7,8-TCDD. Particularly it is suggested that there is a higher risk in soft tissue sarcomas. However, there are uncertainties in the epidemiological data in terms of evaluation of the degree of exposure.

4. Reproductive Effects

2,3,7,8-TCDD causes changes in induction of enzymes and in growth factors, hormones, and their receptors, which result in modulation of the normal homeostasis and hormone balance. They are thus believed to play a role in disrupting endocrine functions.

The toxicity of 2,3,7,8-TCDD in laboratory animals manifests itself more strongly in embryos and fetuses than it does in the mother. Cleft palates and hydronephrosis are typical deformities in mice.

Dioxins cause lower rates of conception and lower birth weights and they affect the estrous cycle. An experiment was conducted over three generations of rats. Effects were observed in the F0 generation at dose of 100 ng/kg/day, and in the F1 and F2 generation at 10 ng/kg/day. Rhesus monkeys were given doses of 5 ng/kg and 25 ng/kg of 2,3,7,8-TCDD in their diet for 4 years, and 71% and 86% of which respectively, showed endometriosis. NOAELs of effects on reproduction are estimated at 1 ng/kg/day based on the 3-generational study on rats, and 0.126 ng/kg/day based on data on rhesus monkeys (5 ng/kg diet).

In experiments of rats where exposed to 2,3,7,8-TCDD while pregnant or nursing, effects on reproductive, thyroid, and immune functions were seen in the ofspring at low levels of exposure. Mably and coworkers found reduction in the weight of reproductive organs and reduction in spermatogenesis in animals given a single dose of 64 ng/kg of dioxins but no follow-up experiments have been done at this dosage to confirm their findings.

Observation of the effects on reproduction and growth in humans has been carried out on groups of people who have been exposed accidentally to dioxins. Studies on the effects of PCDF in a rice-oil poisoning incident in Taiwan, children exposed prenatally to heat degraded PCB mixtures have multiple problems including growth retardation, behavioural deficit, IQ deficit and reproductive functions. Even in groups of people exposed only to background levels of dioxins, it is suggested that there may be links between concentration of dioxins in mothers' milk and changes in thyroid hormones and immune functions in their children and links between dosage levels of dioxins received and low body weight in infants. Furthermore, there is limited but suggestive evidence that exposure of Vietnam veterans to defoliants is linked to an increase in spina bifida in their children.

5. Immunotoxicity

2,3,7,8-TCDD causes atrophy of the thymus through reduction in the number of immature thymus cells. 2,3,7,8-TCDD caused a significant decrease in thymus cells of mice at doses of 100 ng/kg/day.

The defense mechanism against infections of viruses, bacteria, or parasites reacts strongly to doses of 2,3,7,8-TCDD, and increased death rates or slowness at eliminating parasites are observed. Results of experiments in which mice were given single doses of 2,3,7,8-TCDD gave a NOAEL of 5 ng/kg. 2,3,7,8-TCDD suppresses antibody production and causes changes in lymphocytes. Results of single-dose tests on marmosets, a kind of primate being used as an experimental animal, gave a LOEL of 10 ng/kg for changes in lymphocyte subpopulation in the blood.

As to effects on reproductive immune reactions, there are changes in the thymus cell count of the newly born mice when pregnant mice were given 2,3,7,8-TCDD.

Regarding the effects on immunity in humans, epidemiological studies have suggested changes in the level of T-cells, but there is not sufficient data to obtain a conclusion.

6. Toxicity Equivalency Factors

2,3,7,8-TCDD is the most intensively studied congener among dioxins, the toxicity of which has been reported, and there is only limited information available about others congeners. The toxicity of dioxions is determined by the degree and position of chlorine substitution in the molecular ring, and it is thought that toxicity is closely related to the molecule's affinity for the receptor. In consideration of the receptor binding affinity, there was a proposal of a concept of Toxicity Equivalent Factor (TEF), in which the toxicity of other dioxins (congeners of polychlorinated dioxins and polychlorinated dibenzofurans) is estimated on the basis of toxicities of 2,3,7,8-TCDD.

Part 3 Exposure Assessment

1. Situations of Pollution of Dioxins in the Environment

The Environment Agency has been collecting specimens and determined dioxin-related substances in bottom sediments and living organisms from rivers, lakes, and ocean waters of Japan every year since 1985. In its "Follow-up Survey of the Situation of Pollution by Unintentionally Formed Chemical Substances", concentrations of dioxins in rivers were found slightly lower than those in lakes and ocean waters in recent years (see Figures 1 and 2 of this report).

Atmospheric conditions have also been monitored by the Environment Agency's "Studies on Unregulated Atmospheric Pollutants," with a special reference to dioxins. This study has taken measurements every other year since 1986, which show high atmospheric concentrations in residential areas near industrial districts and around large cities. Medium-sized cities showed lower concentrations, and background areas (mountainous regions) showed the lowest (see Figure 3).

The main routes of exposure to dioxins from the environment in Japan are thought to be food, atmosphere, water, and soil. The study of Environment Agency attempted to estimate the amount of exposure through each of these routes. 

Dioxin intake through food in Japan was estimated by Takayama and coworkers in Osaka Prefecture employing "market basket" method, which showed that dioxin intake through food in Japan amounts to 163 pgTEQ/day (see Table 1).

 

The Environment Agency also studied intake of dioxins in nine prefectures employing a method of duplicate food collections. Their results showed an estimated average dioxin intake of 1.25 pg/kg b.w./day (ranging from 0.26 to 3.26 pg/kg/day) (see Table 2).

 

Estimated dioxin intake based on the above two results is given in Table 3. From Table 3, we estimate that the average daily intake of dioxins through food in Japan is 0.26 -3.26 pg/kg/day.

 

Fishes and shellfish

 

Riv. Isikari : Tribolodon hakanensis(1989-1994).

Riv. Kitakami : Tribolodon hakanensis(1989-1994).

Riv. Mogami 1 : Tribolodon hakanensis(1989-1991), Carassius auratus(1992-1994).

Riv.Mogami 2 : Carassius auratus(1989), Tribolodon hakanensis(199O-1994).

Riv. Abukuma : Tribolodon hakanensis(1989-1994).

Riv.Tone : Carassius auratus(1989-1994).

Riv. Shinano : Tribolodonhakanensis(1989,1991-1993), Acanthogobius flavitnanus(199O) Hemibarbus barbus(1994).

Riv.Syouno : Tribolodon hakanensis(1989-1994).

Riv. Kiso : Tribolodon hakanensis (l98g-1994).

Riv.Yodo : Zacco platypus(1989-1994).

Riv. Oyodo : Carassius auratus(1989-1994).

Kasumigaura 1 : Carassius auratus(1989-1994).

Kasumigaura 2 : Carassius auratus(1989~1994).

Lake Suwa : Carassius auratus(1989-l994).

Lake Biwa 1 : Carassius auratus(1989-1994).

Lake Biwa 2 : Carassius auratus(j989-1994).

Sendai Bay : Mugil cephalus(1989-1994).

Offshore of Niigata : Konosirus punctatus(1989), Platycephalus indicus (l990-1994).

Tokyo Bay 1 : Konosirus punctatus (l989-1990, 1992, 1994), Mix of Mugil cephalus and Konosirus punctatus (199l),

Mix of Lateolabrax japonicus and Konosirus punctatus (1993).

Tokyo Bay 2 : Konosirus punctatus (1989),

Lateolabrax japonicus (l990, 1993- 994),

Mugil cephalus(1991-1992).

Tokyo Bay 3 : Lateolabrax japonicus(1989-1994).

Tokyo Bay 4 : Lateolabrax japonicus (1989-1994).

Suruga Bay : Lateolabrax japonicus(1989-1994).

Ise Bay 1 : Mugil cephalus (1989-1994).

Ise Bay 2 : Mugil cephalus (1989-1991, 1993-1994),

Osaka Bay 1 : Lateolabrax japonicus (1989-1994).

Osaka Bay 2 : Mugil cephalus (1990), Lateolabrax japonicus (1989, 1991-1994).

Osaka Bay 3 Lateolabrax japonicus(199-1994).

Osaka Bay 4 : Pleuronectes yokohaniae(1989), Lateolabrax japonicus(1990-1994).

Offshore of Mizushima : Lateolabrax japonicus (1989-1994).

Hirosima Bay : Mugil cephalus (1989-1994).

Kiisuido : Mytilus edulis (l989-1994).

Nagasaki Port : Mugil cephalus (1989-1994).

Hibiki Open sea : Pagrus major (1989, 1991), Stephanolepis cirrhifer (1990, 1994),

Wrasses (1992-1993).

Nakagusuku Bay : Acanthopagrus sivicolus (1989-1994)

 

Fishes and shellfish

 

Riv. Isikari : Tribolodon hakanensis(1989-1994).

Riv. Kitakami : Tribolodon bakanensis(1989-1994).

Riv. Mogami 1 : Tribolodon hakanensis(1989-1991), Carassius auratus(1992-1994).

Riv.Mogami 2 Carassius auratus(1989), Tribolodon hakanensis(199O-1994).

Riv. Abukuma : Tribolodon hakanensis(1989-1994).

Riv.Tone : Carassius auratus(1989-1994)

Riv. Shinano : Tribolodon hakanensis(1989, 1991-1993)

Acanthogobius flavitnanus(199O)

Hetnibarbus barbus(1994).

Riv.Syouno : Tribolodon hakanemsis(1989-1994).

Riv. Kiso : Tribolodon hakanensis(1989-1994).

Riv. Yodo Zacco platypus(1989-1994).

Riv. Oyodo : Carassius auratus(1989-1994).

Kasumigaura 1 : Carassius auratus(1989-1994).

Kasumigaura 2 : Carassius auratus(1989-1994).

Lake Suwa : Carassius auratus(1989-1994).

Lake Biwa 1 : Carassius auratus(1989-1994).

Lake Biwa 2 : Carassius auratus(1989-1994).

Sendai Bay : Mugil cephalus(1989-i994).

Offshore of Niigata : Konosirus punctatus(1989), Platycephalus indicus(1990-1994).

Tokyo Bay 1 :Konosirus punctatus(1989-199O, 1992, 1994), Mix of Mugil cephalus and Konosirus punctatus(1991),

Tokyo Bay 2 : Konosirus punctatus(19~9), Lateolabrax japonicus(199O, 1993-1994),

Mugil cephalus(1991-1992).

Tokyo Bay 3 : Lateolabrax japonicus(1989-1994).

Tokyo Bay 4 : Lateolabrax japonicus(1989-1994).

Suruga Bay : Lateolabrax japonicus(1989-1994).

Ise Bay I : Mugil cephalus(1989-1994).

Ise Bay 2 :Mugil cephalus(1989-1991, 1993-1994), Lateolabrax japonicus(l990).

Osaka Bay 1 :Lateolabrax japonicus(1989-1994).

Osaka Bay 2 : Mugil cephalus(1990), Lateolabrax japonicus(1989, 1991-1994).

Osaka Bay 3 : Lateolabrax japonicus(1989-1994).

Osaka Bay 4 Pleuronectes yokohatnae(1989), Lateolabrax japonicus(199()-1994).

Offshore of Mizushima : Lateolabrax japonicus(1989-1994).

Hirosima Bay : Mugil cephalus(1989-1994).

Kiisuido Mytilus edulis(1989-1994).

Nagasaki Port : Mugil cephalus(19B9-1994).

Hibiki Open sea : Pagrus major(1989, 1991)

Stephanolepis cirrhifer(1990, 1994), Wrasses(l992-1993)

Nakagusuku Bay Acanthopagrus sivicolus(1989-1994)

 

Table 4

 

In addition to the above representative dioxin concentrations, we assumed a daily inhalation of 15 m3 a day for a person of the average weight of 50 kg in calculating intake of dioxin from the atmosphere. The results are given in Table 5.

 

 

Table 5: Estimated Dioxin Intake from the Atmosphere

 

 

Table 5

 

 

 

(Note: Respiration of 15 m3/day, body weight of 50 kg.)

 

 

Intake from soil was estimated according to information on oral intake during childhood and the rest of lifetime and that on absorbed amount through the skin, which is shown in Table 6.

 

2-1-3 Intake from Water

 

According to earlier studies, intake values of dioxins from water were 0.000036~0.00048

pg/kg/day (Miyata) and 0.0004~0.0012 pg/kg/day (Environment Agency), the results of which would be appropriate enough to justify an estimation of 0.001 pg/kg/day for dioxin intake from water.

 

Table 6: Dioxin Intake from Soil (pg/kg/day)

 

2-2 Summation of Dioxin Exposure in the "Average" Environment in Japan

 

Average levels of exposure in dioxins in Japan can be summed up as in Table 7, and could be estimated between 0.3 and 3.5 pg/kg/day.

 

 

Table 7: Estimated Level of Exposure to Dioxins from the "Average" Environment in

 

 

3. Exposure in Environments Deviating from "Average" Environment

 

In order to grasp the overall conditions of exposure to dioxins in Japan, we needed to estimate exposure levels not only in the "average" environment but also in specific situations which deviate from the average environment in terms of different degrees of exposure.

 

The committee presented the following two cases as examples of specific environmental situations deviating from the "average" environment.

 

1) Individuals who have a habit of greater consumption of fish.

 

2) Residents near incineration facilities.

 

Please note that there is a wide variation in actual intake of dioxins among individuals because of differences in regions and eating habits. One must take into account our figures on a certain assumed condition.

 

 

 

3-1 Estimated Exposure by Individuals who consume larger Amounts of Fish

 

3-1-1 Fish Consumption

 

According to the National Nutrition Survey in Japan (1995), the average person consumes 95.2 g daily of fish and other seafood products with a standard deviation of 52.0 g. If we assume that the consumption follows normal distribution pattern,

 

m+ 1.64s__=_ 95.2 + 1.64 x 52.0 = 180.5 g

 

then we can assume that people who eat 180 g or more of fish every day, in other words, two times the average for the population, account for about 5% of the total population.

 

3-1-2 Concentrations of Dioxins in Fish

 

From results of earlier investigations on dioxin concentrations in food fish (see Tables 8-10), i.e. coastal fish and commercially marketed fish (as classified in a study by Setsunan University), shorefish and imported fish (as classified in the study by Ehime University) dioxin concentrations show a great variation. From this, in order to assess exposure to dioxins the kind of fish being consumed or the areas from which they were caught are necessary information to be considered.

 

Taking the above into consideration, we could estimate a dioxin concentration in bay and inland sea fish of about 0.9 pg/g, from a value of 0.90 pg/g obtained by the Ministry of Health and Welfare in an investigation from 1992 to 1995, and a value of 0.89 pg/g in coastal sea fish listed in Table 9 from an investigation carried out by Ehime University.

 

For pelagic fish, we estimate a value of about 0.1 pg/g as a representative concentration, referring to the average concentration of 0.08 pg/g found by Ehime University (see Table 9) for imported fish and a value of 0.01 pg/g found by Setsunan University in an analysis of yellowfin tuna (Thunnus albacares) (see Table 8).

 

Table 5 Concentrations of Dioxins in Coastal fish and Commercially marketed fish (study by Setsunan University)

 

Table 9 Concentrations of Dioxins in Commercially marketed fish (study by Ehime University)

 

3-1-4 Dioxin Intake in Cases of Consumption of Large Amounts of Fish

 

Based on the above observations, we have divided out estimations of exposure in case of larger consumption of fish into two groups below. One must consider that individuals vary in whether or not they continue consuming large amounts of fish in these ways steadily over the long term, and among actual individuals the intake may thus be less than the estimations arrived at here.

 

Referring back to the observations in 3-1-1, it is assumed that people who consume twice the amount of fish as the average person account for about 5% of the total population. Under these circumstances, we also assume that these people do not consume meat or eggs as sources of animal protein.

 

 

(2) When Fish Consumption is Average But Consists Mostly of Bay or Inland Sea Fish

Under these circumstances, dioxin intake is calculated as 1.71 pg/kg/day (=95.2 x 0.9/5). Thus far, because of the limitation of few data for the purpose of estimating intake of dioxins from fish in Japan. Estimations take on a wide variety, but when conditions arc considered overall on the base of averages, using the average of measurements by Takayama, et al., and the Environment Agency, the average intake is shown to be 2.74 pg/kg/day. When calculations are done separately for each set of measurements, the estimation of possible dioxin intake from fish becomes a range from 1.28 to 4.2 pg/kg/day. When other exposure routes are also considered, the overall intake of dioxins becomes an average of 3.59 pg/kg/day, or a range of 1.90-5.28 pg/kg/day.

 

 

Table 11: Estimations of Exposure to Dioxins When Intake from Fish is large.

 

3-2 Exposure in the vicinity of Waste Incinerators

 

In order to estimate the exposure of dioxins near waste incinerators, the committee estimated the maximum concentration near the ground on an average annual basis, using a dispersion model for exhaust gas emitted from waste incineration facility stacks.

 

3-2-1 Types of Incineration Facilities and Predicting Dispersal Concentrations

 

The committee divided waste incinerators into 47 different types based on furnace type, cooling type, pollution control measurement, exhaust gas treatment methods, stack height, etc. Thus we think we covered nearly all conditions of general waste incineration facilities.

 

For each type of facilities the committee estimated the annually averaged maximum concentration of dioxins at ground level that is associated exhaust gases from the stacks. Furthermore, in addition to cases with average dioxin concentrations in the exhaust gas, the committee considered cases in which the exhaust gas had dioxin concentrations of twice the standard deviation above the average, looking at exhaust gas distribution cases from waste incinerators in operation (Interim Report Vol. 4 of committee to Consider Measures to Eliminate Dioxin Arising from Waste Management, Ministry of Health and Welfare). Conditions assumed in this case were average conditions of mechanized batch method and independent stack facilities.

 

When the concentration of dioxins in discharged gas is average, in cases where countermeasures are being taken against dioxin discharge, the maximum concentration at ground level averaged over a year is calculated to be 0.01-0.8 pg/m3, and in cases where countermeasures are not taken against dioxins, it is 0.2-1.9 pg/m3. In cases where the concentration of dioxins in discharged gas are higher than the average, the maximum concentration at ground level averaged over a year is calculated to be about 3 pg/m3. In addition, the committee calculated estimations of falling dust from the atmosphere using the dispersion model.

 

3-2-3 Establishing Concentrations in the Ambient Air Near Waste Incinerators

 

Based on the predicted dispersion concentrations and the atmospheric concentrations in and around large cities (Table 4), the committee estimated atmospheric concentrations near waste incineration facilities of 3-4 pg/m3. The amount of falling dust was calculated, based on the dioxin concentration at ground level at the point where the maximum concentration is given. Estimations were based on actual measurements of concentration of dioxins in soil near facilities where industrial waste materials had been incinerated.

 

 

From the above, total intake of dioxins of a person in the vicinity of a waste incineration plant has been estimated as shown in Table 12.

 

Part 4: Risk Characterization of Dioxins

 

1. Evaluation of Health Effects

 

1-1 Overview

 

From the results of experiments with laboratory animals, dioxins have been found to be toxic in a wide variety of ways, including acute toxicity, chronic toxicity, carcinogenicity, reproductive toxicity, teratogenicity, and immunotoxicity. Not all of these forms of toxicity were observed in a single animal species, but vary according to species, strains, age, and sex.

 

As to the effects on humans reported so far by the epidemiological studies, it was reported that excessive exposure to dioxins in the occupational settings and by accidents results in severe chloracne, and other effects such as hepatotoxicity, neurologic and pulmonary symptoms. As chronic health effects, chloracne is widely observed, but there is no accurately proven reports on endocrine and other toxicities. However, as to carcinogenicity the Working Committee of IARC held in February 1997 revealed their view that only 2,3,7,8-TCDD among dioxine congeners should be classified as human carcinogen (Group 1) although the IARC assessed until recently that the compound should be considered to be possible carcinogen (Group 2B)(see Note). And other congeners of dioxins were thought to be unclassifiable by the IARC committee. In the present committee of the Environment Agency, 2,3,7,8,-TCDD was not separated from other congeners, and risk assessment was performed for dioxin congeners.

 

According to the currently available data, mutagenicity of dioxins were found to be negative and no genotoxicity was thought to be present, and Ah receptors are considered to be responsible for the manifestation of toxicity of dioxins. Taken together, the present committee concludes that it would be appropriate to assume that dioxins have a threshold in the process of carcinogenesis.

 

(Note) It is reported that, as the rationale to derive this conclusion, the Working Committee of IARC considered that despite limited epidemiological data 2,3,7,8-TCDD causes multi-organ cancer in laboratory animals, that the carcinogenic mechanism found in laboratory animals may probably occur in a similar fashion in humans, and that 2,3,7,8-TCDD concentrations in the tissues were similar each other between the human subjects who had a higher risk to all types of cancers and had high level exposure and the rats that had cancers.

 

To evaluate the risks of dioxins, the committee reviewed results of experiments on various kinds of animals which differently respond to dioxins. As a basis of discussion we chose four results of experiments described below in which effects were observed at the lowest levels of exposure. In other experiments, effects were observed at higher levels.

 

Toth performed an experiment with Swiss strain mice, giving them oral doses for one year. Amyloidosis and dermatitis were observed in the males given a minimum of 7 ng/kg/week (=1 ng/kg/day), which was thought as LOAEL in this strain of mouse. The present committee pointed out that it is not clear how significant the amyloidosis and dermatitis seen in mice in this experiment are with regard to dioxin's impact on human health. Furthermore, there are no countries which adopt the result of this experiment as a basis of the standard of dioxin intake.

When Rier conducted laparoscopie examination in rhesus monkeys, endometriosis was seen in the control group at a rate of 33%, but at a rate of 71% in a test group given diet containing 5 ng/kg of dioxins (126 pg/kg/day) and at a rate of 86% in a test group given diet containing 25 ng/kg (630 pg/kg/day). When endometriosis was classified according to severity, the control group had no cases of medium or higher severity, but both test groups did, at rates of 43% and 71%, respectively, showing a significantly higher tendency to develop severe cases. The results of this test gave LOAEL of 126 (100-180) pg/kg/day, the lowest level of exposure at which effects have been seen.

 

There is also a set of data on rhesus monkeys from the results of the following experiments. Allen and coworkers gave eight female rhesus monkeys 50 ng/kg in their diet over a seven-months period (1260 pg/kg/day). Of these eight monkeys, six monkeys became pregnant, but four miscarried, and of the two that gave birth, one did so prematurely. Only one of the eight managed to give a normal birth.

 

When Bowman and coworkers gave rhesus monkeys 5 ng/kg in their diet (126 pg/kg/day), they noticed no significant differences between the experiment group and the control group, but they reported that when they gave 25 ng/kg in the diet of eight rhesus monkeys over seven months (630 pg/kg/day), three failed to conceive; and of the five that conceived, three miscarried and one had a death in utero. Only one of the eight gave a normal birth.

 

The committee agreed that the endometriosis observed in Rier's experiment is a cause of miscarriage and infertility, which is related to the endpoints observed in the above two experiments, and that the result on miscarriage and infertility is an important data in support of Rier's conclusions.

 

Since Rier's experiment showed a dose-dependent relationship, the committee considered that its results must not be overlooked because they provide data on primates, the animals most similar to humans in terms of the half-life and the body burden of dioxins there have been no follow-up study so far which Support the conclusions of Rier's experiment. Nevertheless,the committee pointed out that the high incidence of endometriosis in the control group makes it a little to directly use the data for evaluation of health effects of dioxins in humans.

 

Health effects such as chloroacne have been focused as an effect of dioxins in humans. Epidemiological data on dioxins have been collected through investigations on victims of accidents and occupational exposure and on veterans who were engaged in herbicide scattering operation in Viet Nam War.

 

Records of poisonings of humans by furans include cases of rice oil contamination in Japan and Taiwan. In the case of the poisoning in Taiwan, infants exposed through their mothers' milk or via the placenta were reported to show developmental problems such as delayed physical or sexual development or lower IQ's as well as an effect on the immune system, but the number of cases was small and no firm evaluation could be obtained.

 

1-2 Establishing Health Risk Assessment Guidelines

The committee considered that exposure of people to dioxins occurs mostly as a result of environmental pollution, and that in order to prevent health effects environmental pollution levels due to dioxins must be lowered. Thus the committee decided to establish health risk assessment guidelines to be used when formulating countermeasures to protect the environment. This is not the allowable limit for the human health, but rather the desirable concentration to be maintained for the use of evaluating exposure in humans.

1-2-2 Establishing Health Risk Assessment guidelines

 

In consideration of the above points, the committee considered that it would be appropriate to establish health risk assessment guidelines, using Kociba's data for a start. Although, the committee thought that it would not be appropriate at this time to utilize epidemiological data for calculations of the guidelines, epidemiological investigations will be continuously performed, and their prospective results are certain to merit attention.

Using Kociba's results, the committee obtained a value of 10 pg/kg/day, the value of which is similar to the values that other countries obtained using Kociba's data (or Murray's data) under the condition that dioxins have the threshold limit. The research group of Ministry of Health and Welfare also used this value as TDI.

 

Based upon the purpose of the health risk assessment guidelines, the present committee concluded that in establishing these guidelines it would be appropriate to consider not merely preventing cancer but also related effects and other conditions deviating from health. From this point of view, the committee considered that Rier's data on endometriosis in rhesus monkeys shows a dose-dependent relationship, and that involvement of hormones or the immune system is plausible, and there has been shown to be a connection with Ah receptors in the occurrence of this disease although the mechanism for development of endometriosis in these cases is not clear. The committee agreed that the results of this experiment must be considered in establishing the guideline for evaluating health risks. However, the committee also recognized that in light of remaining problems as noted in the above-mentioned Rier's results, there is still a room for consideration to derive a guideline value directly from this experiment. On the other hand, for the reasons stated above, it would be inappropriate to exclude Rier's study from consideration and this experiment should be fairly evaluated for assessing health risks due to dioxins. The committee also decided it would be appropriate to create a safety margin for the guideline of health risks at 5 pg/kg/day, half the value 10 pg/kg/day derived from Kociba's data.

 

The committee considered that there have been no clear scientific data so far which support to establish a value lower than 5 pg/kg/day. Therefore, the committee concludes that it is best at this time to use this value as the guidelines for assessing health risks. However, there are other reports not discussed here which show the possibility of some kinds of health risks in experiments using even lower dosages. Therefore, we need to make an effort to reduce the risks from dioxins further and to collect more scientific knowledge on this problem.

 

2. Exposure Assessment

In order to evaluate risks from dioxins, the committee made the following estimations to get an overall grasp of conditions related to exposure in Japan.

 

2-1 Exposure in the General Environment in Japan

 

The committee estimated the average amount of exposure, assuming a typical living environment in Japan. As a result, the committee estimated exposure to be 0.3-3.5 pg/kg/day. However, the committee concludes the actual level of exposure in individuals can vary considerably with different dietary habits and among different areas.

 

2-2 Exposure in Environments Deviating from the General Environment in Japan

 

In order to estimate the possible deviation from the average levels of exposure found in 2-1 for dioxin pollution conditions in Japan, the committee thought of the following examples of living environment deviating from the typical general environment.

 

1) When we assumed a situation of eating a relatively large amounts of fish ,we obtained a value of 3.6 (1.9-5.3) pg/kg/day, for the estimated exposure to dioxins under these circumstances.

 

2) When we estimated exposure in the vicinity of incineration facilities, one of the major sources of dioxin in Japan, we obtained a value of 1.8-5.1 pg/kg/day.

 

From the results obtained in both 1) and 2) above, it can be assumed that there may be such

cases of exposure to as much as 5 pg/kg/day under circumstances in which people have greater exposure than the average as the result of dioxin pollution occurring currently in Japan.

 

Furthermore in the case of both 1) and 2), the estimations were based on standardized conditions for each example although there would be various forms of exposure to dioxins occurring, and just as mentioned in 2-1 above, actual levels of exposure in individuals are thought to vary considerably with region and dietary habits.

 

With regard to exposure assessments in 2-1 and 2-2, estimations were made in spite of absence of sufficient data on the concentration of dioxin in the diet and in the general environment. More data need to be collected in the future.

 

3. Overview of Risk Assessment

 

Based on the above conclusions, the risks associated with dioxins in Japan can be assessed as follows.

 

3-1 Since estimated values of exposure to dioxins were lower than our health risk assessment guidelines in the general environment in Japan, we think that there is little possibility of dioxins having much effect on human health at this time. However, the current exposure levels cannot be said to be sufficiently lower than the guidelines, and from the viewpoint of ensuring a high degree of safety over the long term, the committee concludes it would be desirable to take measures to decrease dioxin concentration in the environment.

3-2 Under circumstances where exposure to dioxins is particularly high in comparison with the exposure levels in the average environment as the result of current pollution with dioxins, there are probably cases in which estimated exposure is the same as or slightly higher than the guidelines for assessing health risks. From the viewpoint of reducing health risks in the future we think it is necessary to take measures to lessen dioxin concentration in the environment.

 

Part 5: Other Items Considered

 

1. Intake from Breast Milk

Dioxins are known to be secreted into the milk of nursing mothers, and the levels of concentration in mothers' milk are about the same in Japan as those in other developed countries. On the other hand, there is clear evidence of the benefits of mothers' milk on the health of babies, and following the lead of the WHO, we believe breast feeding should be promoted. Therefore we deem it appropriate for breast feeding to continue in Japan, and in order to ensure the continued safety of mothers' milk appropriate policies should be supported for taking countermeasures to pollution sources and promoting research.

 

Since there has been a shortage of data on concentrations of coplanar PCBs in the environment and the values for coplanar PCBs are not necessarily agreed, it is difficult to perform exposure assessment of coplanar PCBs accurately. The toxicity of coplanar PCBs follows a similar mechanism to that of dioxins, and much attention must be given to their risks to human health, and research and discussion need to be focused further on their toxicity.

MEMBERS AT ADHOC COMMITTEE ON DIOXIN RISK ASSESSMENT

Ikeda Masayuki Professor Emeritus, Tohoku University

Ikeda Masayuki Professor Emeritus, Tohoku University

Sakurai Haruhiko Professor of Medicine, Keio University

Shimizu Makoto Professor Emeritus, Tokyo University

Suzuki Tsuguyoshi Former Head of National Institute for Environmental Studies (Chairman)

Masuda Yoshito Professor, Daiichi College of Pharmaceutical Sciences

Miyata Hideaki Professor of Pharmaceutical Science, Setsunan University

Yasuda Mineo Professor of Medicine, Hiroshima University

Yoshimura Hidetoshi Professor, Nakamura gakuen University