情報：農と環境と医療36号

It is my honor to welcome you to Kitasato University's 4th Agromedicine Symposium.

Dr. Shibasaburo Kitasato has made immeasurable contributions to the development of modern medicine and health services in Japan. Dr. Kitasato began his "Idoron (Medical Ethics)" (1878), which he wrote when he was just 25 years old, by expressing his belief in medical ethics:

"Ancient people said medicine is the healing art. They also said it is virtue that a great doctor heals the nation. Medicine in its true form is to help people maintain their health, work with peace of mind, and develop an affluent and strong nation. If one knows no good regimen, he cannot maintain his body in good health. Without health, living is hardly meaningful...fundamental to medical ethics is for practitioners to help people understand how important health is so that they will take care of hygiene and prevent illnesses before they strike."

Dr. Hisayuki Omodaka, who lectured at the medical faculty of Kitasato University in its early years, was deeply involved in the "Principles of Medicine" course that is presently offered at the faculty. In his book "Igaku Gairon Towa (An Outline of Medicine)" (Seishin Shobo, 1987), Dr. Omodaka roughly says this:

What does medicine study? Not the philosophy of life. Not the ethics of medicine (although it is part of the outline of medicine). Not just medical ethics. Medicine considers not only the phenomena of physical life but also spiritual phenomena. Medicine cannot be just one of the natural sciences. It must be a social science as well. Medicine is knowledge of as well as the art of healing illnesses. Medicine studies not only the ways to treat or prevent illnesses, but also the ways to maintain health. Medicine is, however, not only a discipline for maintaining health. It must be a discipline for willingly improving health.

These books by Drs. Kitasato and Omodaka tell us that medicine is a discipline that should encompass the treatment and prevention of illnesses, the maintenance and improvement of health, as well as the solution of spiritual aspects. In order to fulfill these mandates, it is important for us to maintain wholesomeness and safety of food (agriculture) and the environment that are the basis for the life. These books tell us that people cannot be healthy without wholesome food and a sound environment. Our predecessors have already spoken of the need for a science in which agriculture and medicine collaborate through environmental efforts.

From these perspectives, we at Kitasato University, which aims to be at the frontier of life science, promote the close collaboration of agriculture, environment and medicine. We direct our efforts in education and research to the issues pointed out by our predecessors, as well as new issues, such as infectious disease, food safety and global warming, that modern society faces today. The Kitasato University Agriculture and Medicine Symposium is part of our efforts.

The 4th symposium focuses on the behavior of arsenic and cadmium from the perspectives of food safety, biogeochemistry, soil, plants, clinical environmental medicine and law. We hope the symposium will help in the development of the collaborative science of agriculture and medicine.

During the symposium, we hope you will engage in meaningful and practical discussions that will lead to new ideas and suggestions for dealing with health issues arising from issues relating to food and the environment. We would like to extend our sincere appreciation to those of you who have agreed to speak at the symposium.

All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy.
 Paracelsus (1493-1541)

Introduction

The modern civilization in which we live today depends on a tremendous quantity of heavy metals to exist. History shows a close correlation between the evolution of humankind and the consumption of heavy metals.

Humans began using copper in 6000 BC approximately, lead in 5000 BC and zinc and mercury in 500 BC. These events are evidenced by analyses of heavy metals contained in sediments, cores of polar ice and peat. History has proven the impacts of heavy metals on environment. It has been also verified that the Roman Empire used a considerable quantity of lead.

With the start of the Industrial Revolution in the 19th century, heavy metals became increasingly essential to modern society. As a result, the types and quantities of heavy metals extracted from the earth increased, inevitably leading to exponential increases in these metals being dispersed into the soil, vegetation, ocean and atmosphere. This began to disrupt the biogeochemical cycling of heavy metals.

What does the disruption of the biogeochemical cycle of heavy metals mean? Heavy metals that have been going through steady cycles would begin to impose an excess load on the atmosphere, soil and ocean. These excess heavy metals loaded into soil are absorbed by crops. The heavy metals dispersed in oceans are taken up by the fish and shellfish that live in the waters.

As a consequence, humans and animals that eat these crops, fish and shellfish begin to accumulate higher-than-normal amounts of heavy metals in their bodies. These heavy metals will pass down through future generations of humans and animals. The heavy metals will accumulate in humans through the food chain. It is an accumulation that will span generations. Heavy metal contamination is a problem that transcends time and space.

The purposes of agriculture and agronomy are to supply people with safe and sufficient food as well as biological resources for things such as clothing. In order to ensure these purposes are met, we must preserve the environment. The purposes of healthcare and medicine are to save people from diseases and to protect their health. In order to ensure these purposes are met, we must preserve the environment just as much as agriculture and agronomy are expected to. We cannot ensure production and health if we ignore the environment.

Many factors impede the production of food and biological resources, contribute to illnesses or adversely affect our health. One of the key factors is the contamination of the environment by toxic metals.

Some of these toxic metals, such as cadmium, may be toxic to animals, including humans, even at concentration levels that do not inhibit the growth of plants. As a consequence, the contamination of the environment by toxic metals is an issue that agriculture and agronomy, as well as healthcare and medicine, cannot sidestep.

Although localized, we have been unfortunate enough to experience this problem in illnesses such as the itai-itai disease caused by cadmium poisoning and the Minamata disease caused by mercury poisoning. Events such as these have the potential to occur everywhere on earth in the future.

The Codex Alimentarius Commission created jointly by FAO and WHO has already established international standards for food and legislated regulations of cadmium and other heavy metals in food.

It is essential for all life existing on earth for heavy metal concentrations to be limited to appropriate levels. This is particularly true for food that animals and humans consume. Heavy metals dispersed from the earth's crust into the natural world in the soil, ocean and rivers will ultimately be accumulated in human bodies through plants, fishery products and animals. Accordingly, we need collaborative studies among agriculture, environment and medicine to find solutions to these heavy metal problems.

This article will survey the behavior of cadmium and arsenic from the perspectives of biogeochemistry, soil, plant, clinical environmental medicine and law in the hope of assisting the collaborative science of agriculture and medicine.

Development of civilization and the dispersion of heavy metals

Many fields of studies are increasingly casting a spotlight on heavy metals as environmental problems become more global. To put it in a few words without fear of misunderstanding, humans have been mining large amounts of metals from the earth's crust and dispersing then over the earth's surface as their civilizations developed. Demand for metals accelerated at an unprecedented pace particularly during the Industrial Revolution. Until then, heavy metals had remained deep in the ground since time immemorial, quietly asleep.

A look at history tells us that humankind owes its development to heavy metals to a great extent. Modern civilizations could not have been established without large amounts of heavy metals. Analyses of heavy metals contained in sediments, cores from polar ice sheets and peat reveal the extent of the impact that heavy metals have had on the environment.

The Roman Empire needed massive amounts of heavy metals for its citizens to maintain their comfortable and lavish life. The Romans consumed 80,000 to 100,000 tons of lead, 15,000 tons of copper, 10,000 tons of zinc, and more than 2 tons of mercury annually. Tin was also in high demand. Mine business was small at that time but their smelting operations processed a large amount of ores in uncontrolled open systems, dispersing considerable amounts of trace metals into the atmosphere. This led to increasing types and amounts heavy metals that were mined from the earth's crust, inevitably resulting in increased dispersion into the soil, vegetation, oceans and atmosphere.

As a matter of course, the growth of world population and increases in heavy metal consumption that accompanied the growth resulted in dispersal of heavy metals into the natural world, creating a variety of ecological problems. Many of the heavy metals contained in soil, water and living organisms are essential for a healthy life, even though excessive concentrations have toxic effects on living systems. It is, therefore, important for us to know the appropriate concentration levels of heavy metals in living organisms that exist in nature, as well as in food that animals and humans consume. Heavy metals that were dispersed in nature will be ultimately accumulated in the human body through soil, vegetation and animals. Accordingly, it is also important to accumulate knowledge of the behavior of these heavy metals in soil. Indeed, this is an issue that requires collaborative studies among agriculture, environment and medicine.

Comparison of past and present distributions of heavy metals

Here are some specific numbers. A study by Hong et al. (1994) found that the ice sheet cores deposited in northwestern Greenland between 500 BC and 300 AD contained lead at a level that was 4 times higher than the background. This means that the contamination by lead dispersed from Roman mines and smelters spread over the Northern Hemisphere.

The lead content decreased to an earlier level (0.5 pg/g) after the fall of the Roman Empire, but began to increase again with the mining renaissance in Europe, reaching 10 pg/g in the 1770s, and 50 pg/g in the 1990s. The lead content in the arctic snow began to decrease in the 1970s, due perhaps to a switch to unleaded gasoline in North America and Europe.

Lead contamination of the atmosphere is not limited to the Northern Hemisphere. Woff and Suttie (1994) reported that the average accumulation of lead in the arctic snow during the 1920s (2.5 pg/g) was 5 times higher than the background level (less than 0.5 pg/g). The lead content is lower in Antarctica because the Southern Hemisphere generates less lead.

Studies of other types of sediments also revealed that lead contamination occurred on a global scale in ancient times. An analysis of sediments in various lakes in Sweden indicates that there was a peak in the build-up of lead around 2000 BC. The build-up gradually increased around 1000 BC, and reached a level that was 10 to 30 times higher than the background in the early days of the industrial revolution. The build-up of lead accelerated in the 19th century, and peaked in the 1970s (Renberg et al., 1994).

The records regarding ombrogenic bogs in Etang de la Gruere in Switzerland reveal that the lead build-up at its peak in 2000 BC was at the same level as it is in recent sediments. Similar peaks of build-up of lead in Roman times have been reported for European peat bogs, such as the Gordano Valley near Bristol and the Featherbed Moss in Derbyshire in England.

The world is being contaminated by a variety of metals. Indeed, it is a difficult time for us to fulfill our ethical objective of preserving a healthy environment for future generations. The following section will discuss cadmium and arsenic, which have had a large impact on human health. These substances have been investigated as the causes of environmental diseases, and reviewed by the Codex Alimentarius Commission as elements in food.

Cadmium and arsenic

There are four diseases in Japan that are officially recognized by the Ministry of the Environment of Japan as pollution-related diseases. They are itai-itai disease caused by cadmium (187 designated victims), chronic arsenic poisoning (188 victims), Minamata disease caused by organic mercury (2,995 victims) and respiratory diseases caused by air pollution (53,502 victims).

Of various pollution-related diseases addressed by the 4th Kitasato University symposium, cadmium and arsenic are the most discussed substances. They have been discussed at numerous symposia and investigated by numerous studies. There are a large number of reviews as well. Yet few attempts have been made at integrating the knowledge of biogeochemistry, agronomy, soil science, environmental science, clinical environmental medicine and law in any comprehensive form.

I will present to the symposium how cadmium and arsenic are linked through biogeochemistry to agronomy and soil science. The following section is a brief look at examples of arsenic and cadmium contamination around the world and in Japan.

Arsenic and cadmium contamination in the world and Japan

1) Regions with arsenic-contaminated aquifers, mines and geothermal water

Arsenic contamination of aquifers:United States (Western states), Mexico (North central, Lagunera), Chile (Antofagasta), Argentina (Chaco-Pampean Plain), Hungary-Romania (Great Hungarian Plain), Nepal (Terai area), China (Shanxi, Gui Zhou Province, Inner Mongolia, Shanxi, Xinjiang-Uygur Autonomous Region), Bangladesh (West Bengal), India (West Bengal), Vietnam (Red River delta), Cambodia (Mekong River), Myanmar (Ayeyarwady River), Pakistan (Indus River), etc.

Arsenic contamination caused by mining:Alaska (Fairbanks), Canada (British Columbia), seven regions in the United States (Coeur d'Alene, Clark River, Lake Owen, Wisconsin, Halifax County, Badger, Don Pedro), Mexico (Zimapan Valley), Brazil (Minas Gerais), Ghana (Asanti), Zimbabwe, England (Southwest), Poland (Southwest), Austria (Styria), Greece (Lavrion), Korea (Gubong), Thailand (Romphibun), Indonesia (Sarawak), etc.

Arsenic contamination of geothermal water:Dominica, El Salvador, USA (Alaska, western states), Chile (Antofagasta), Argentina (Northwest), France (Massif Centrale), New Zealand (Wairakei), Russia (Kamchatka), Japan (Miyazaki, Shimane), etc.

2) Areas designated for remediation projects for cadmium-contaminated soil in agricultural lands in Japan

As of March 2006, there are 60 areas in Japan that are designated for remediation projects for cadmium-contaminated soil in agricultural lands. The areas total 6,228 hectares. The concentration of cadmium in brown rice in these designated areas exceeds 1.0 mg/kg. The areas are situated in 22 prefectures, from Akita in the north to Kumamoto in the south. To date, remedial projects have been completed for 90% of the designated areas covering 5,618 hectares.

3) Areas designated for remediation project for arsenic-contaminated soil in agricultural lands in Japan

There were 14 areas (totaling 391 hectares) across Japan where the detected concentrations of arsenic exceeded the standard prescribed by the Soil Contamination Control Act. Seven areas, totaling 164 hectares, were designated for remediation projects to clean up contaminated soil in agricultural lands as of March 2006. The status of these projects are described below. The arsenic concentrations in the soil of the designated areas exceeded 15 mg/kg.

Areas designated for soil remediation projects: Township of Kawauchi, Shimokita-gun, Aomori Prefecture (13.5 ha; site delisted), city of Ota, Shimane Prefecture (7.3 ha; site delisted), city of Masuda, Shimane Prefecture (27.3 ha; site delisted), township of Tsuwano in Kanoashi-gun, Shimane Prefecture (66.1 ha; project completed), township of Ato, Mine-gun, Yamaguchi Prefecture (8.4 ha; site delisted), township of Ogata, Ono-gun, Oita Prefecture (27.7 ha; site delisted) and township of Takachiho, Nishiusuki-gun, Miyazaki Prefecture (13.5 ha; project completed).

Of these designated areas, the prefectures of Shimane and Miyazaki have 21 and 167 persons, respectively, who have been designated as the victims of pollution-related chronic arsenic poisoning.

Introduction

From the discovery of mines early in the 8th century, metal mining in Japan grew into an industry from the late Middle Age to the early Modern Age. The Edo Period saw mine developments flourish. It was not until after the Meiji Restoration when the Japanese mines began to take the form of modern corporations. Major mines expanded under the direct control of the government during this period. Demand for copper and zinc as raw materials for weapons increased considerably, and so did the output of ores from mines. The demand for metals rose again after the Second World War because of the Korean War, and then accelerated in response to the high economic growth that began in the 1960s. Large volumes of metal ores were mined from the earth and refined in order to satisfy the increasing demands of society. Ore imports also began to increase to make up the shortfall in domestic production. Through these periods, various heavy metals were discharged into the environment in Japan, resulting in wide-spread contamination of the soil by cadmium and other heavy metals. Such contamination is a negative legacy of past human activities, which is demanding the expenditure of considerable funds and labor today for mitigation.

1. Heavy metal contamination of soil in agricultural lands

Although there is no accurate definition of what constitutes a heavy metal, a generally accepted collective term describes it to be a metal with a specific gravity above 4 to 5. The heavy metals that contaminate soil include cadmium (Cd), copper (Cu), arsenic (As), zinc (Zn), lead (Pb), mercury (Hg), antimony (Sb) and chromium (Cr).

Most of the contamination of soil by heavy metals originates in the contamination of water or air. Once the soil is contaminated, removal of the heavy metals is not an easy task.

The Agricultural Land Soil Pollution Prevention Act of Japan, enacted in 1970, designated copper, cadmium and arsenic as special toxic substances. Major incidents involving these three metals in the past, which caused soil contamination, are as follows:

The so-called Ashio Mine Poisoning Case, in which paddy fields and the croplands of the Watarase River basin were contaminated by copper discharged from the Ashio Copper Mine. This case, occurring in the mid-Meiji Period, is regarded as the beginning of pollution problems in Japan. In another case, cadmium discharged from the Kamioka Mines at the upstream Jinzu River was found to be the cause of the itai-itai disease that emerged among the residents of the river basin. Later, many more cases of cadmium contamination of the soil in agricultural lands in river basin areas with mines upstream emerged across the country. Flue gas from zinc and copper smelters contaminated the soil in neighboring farms with cadmium. Arsenic discharged from some of the mines in the Kyushu and the San'in Regions contaminated the soil in farmlands around the mines and impacted the growth of rice. Contaminated well waters affected the health of the residents.

The Ministry of the Environment (the former Environment Agency) continues to conduct surveys of the concentration of these three elements in farmland soil. Remedial measures, such as soil dressing, are being implemented through special soil remediation projects. Cadmium is the heavy metal that has caused the most serious contamination problems in recent years. Abatement programs are urgently needed.

2. The state of cadmium contamination and remediation

1) World trends in cadmium-related risk management

Although cadmium is not an essential element for plants, some plants take up cadmium through their roots and transport it to their edible parts. When the link between itai-itai disease and cadmium contamination became apparent in 1968, the then Ministry of Welfare and Health (now the Ministry of Health, Labor and Welfare; MHLW) revised the specifications and standards for food and food additives in 1970 to limit cadmium concentration in unpolished rice to less than 1.0 mg kg-1 under the Food Sanitation Act. At the same time, the Food Agency, as it was then known, set policy that the government would not purchase unpolished rice with cadmium concentrations exceeding 1.0 mg kg-1. The policy also stipulated that the use of unpolished rice with a cadmium content of less than 1.0 mg kg-1, which was deemed fit for purchase by the government, would be limited to non-food processing (e.g. industrial glue) if the cadmium concentration was more than 0.4 mg kg-1. The Agricultural Land Soil Pollution Prevention Act came into effect in 1971; under this act, remediation projects using soil dressing were carried out for paddy fields that produced unpolished rice with a cadmium concentration of more than 1.0 mg kg-1.

According to a survey by the Ministry of the Environment, the total area of farmlands designated as cadmium-contaminated areas across the country exceeded 6,000 hectares. Remediation has been completed on more than 80% of these lands to date, with remediation efforts continuing in the remaining areas.

Cadmium contamination of foods became a global issue in the 1960s. In 1998, the Codex Alimentarius Commission (a joint food standards commission of FAO and WHO; the Codex) developed a preliminary draft proposal to regulate cadmium concentrations in agricultural products.

The Codex continued to review its proposal on an annual basis, and adopted the proposed standards for wheat, potatoes, legumes (except soy beans) and vegetables at its general meeting in 2005. The 2006 general meeting of the Codex set the standard for polished rice at 0.4 mg kg-1.
2) Soil remediation technologies

(a) Soil dressing

Soil dressing is an effective engineering technique, which aims to separate the roots of crops from the contaminated soil by introducing non-contaminated soil to the land. It is, however, costly and difficult to secure necessary material (i.e. non-contaminated soil).

(b) Water management and use of materials to inhibit cadmium absorption by rice plants

When the soil is in a reduced condition under flooded paddy fields, cadmium loses much of its water solubility as it binds to sulfur and becomes cadmium sulfate (CdS); when the soil is in an oxidized condition after water is taken out, cadmium is ionized as cadmium sulfate (CdSO4), and dissolves in water. In other words, maintaining the paddy fields flooded to the extent possible to prevent the soil from drying could prevent cadmium from dissolving into the water. As a result, rice plants will take up less cadmium.

(c) Phytoremediation

Some plants have been known to take up cadmium effectively from the soil. For example, the tall golden rods of the chrysanthemum family and field pennycress of the mustard family are said to take up considerable amounts of cadmium. Sorghum of the Poaceae family and kenaf of the hibiscus family have been cited as other examples in recent years. Cadmium in the soil may be removed by growing these plants in contaminated agricultural land and allowing them to take up the chemical. This technique is called "phytoremediation", and is receiving considerable attention as an environmentally-friendly soil remediation technology.

The National Institute of Agro-Environmental Sciences (NIAES) recently found some varieties of rice in indica and japonica-indica hybrid cultivar groups that take up large amounts of cadmium. NIAES is currently investigating its availability for use in phytoremediation. The plants cultivated as part of a phytoremediation project will be harvested, transported away from farmlands and incinerated. The cadmium will be recovered from the ash.

(d) Chemical cleansing of soil

There is a method for the elimination of cadmium from soil by washing the contaminated soil with materials such as ferric chloride and water. After the cleansing, cadmium that was released to the surface of paddy water is collected by pump, filtered and recovered using a chelating resin. Rice will grow normally in the cleansed paddy fields and the cadmium concentration in unpolished rice will decline.

3. Contamination by lead, arsenic and other metals

1) Contamination by lead

Studies of isotope ratios of lead revealed that lead contained in exhaust gas emitted by motor vehicles burning leaded gasoline until the 1970s was a major cause of contamination of the soil along the roads. The uptake of lead by crops is generally very small. Crops grown in soil with a high lead concentration tend to have a relatively higher lead content, with the most concentrated lead in the root. Lead rarely migrates above the ground, especially into the fruits. Deposition from the atmosphere rather than uptake from the soil was blamed for the lead contamination of leafy vegetables.

2) Contamination by arsenic

In some areas in Japan detected arsenic content exceeds the standard prescribed by the Soil Pollution Prevention Act total 14 (391 ha). Of these areas, seven (164 ha total) were designated as areas requiring remediation under the law. Although arsenic inhibits the growth of rice in arsenic-contaminated paddy fields due to its toxicity, it rarely migrates to unpolished rice, except for some organic arsenic that appears to be taken up rice plants. Recent studies have detected diphenylarsine (DPAA) and phenylmethylarsine (PMAA) in unpolished rice grown in organic-arsenic contaminated paddy fields. Yet, it is scarcely known how rice plants take up organic arsenic.

3) Contamination by other heavy metals

Other heavy metals that are of concern to humans as soil contaminants are zinc, copper, mercury, antimony and chromium. Zinc and copper are essential elements for both plants and animals, and pose little threat to crops unless their concentrations reach a very high level. As plants take up little mercury, antimony and chromium, these metals in soil of agriculture lands are of little concern with respect to crop contamination.

1. Introduction

Man needs nutrients to grow and maintain a healthy body. We obtain essential nutrients mainly from food. Yet, we need a large amount of water, and therefore, we ingest components that are dissolved in the water through the mouth in the same way as food. Heavy metals enter the human body as minerals contained in food, and as heavy metals dissolved in water (Fig. 1).

Some of the heavy metals that enter the human body, such as iron (Fe), zinc (Zn), copper (Cu), trace amounts of chromium (Cr) and selenium (Se), are essential nutrient minerals, while others, such as cadmium (Cd) and arsenic (As), are toxic to humans. Heavy metals enter the human body primarily through food and water. Those entering through water are in the form of free ions dissolved in the water, while those entering through foods are bound to components of the food. As illustrated by Figure 1, most of our food, except fish and shellfish, is produced in agricultural lands. Food grown in agricultural lands directly enters our mouth. Feed consumed by livestock also enters our mouth indirectly as livestock productsFoods and animal feeds are grown in the soil of agricultural lands. The soil contains heavy metals that exist in nature as well as those that enter the soil through irrigation and fertilizers. All are taken up by crops.

Living plants take up essential trace elements such as Fe, Zn and Cu, for their growth and maintenance of their functions. The plants also take up non-essential heavy metals, such as cadmium and arsenic, from the environment (i.e. soil), (Fig. 2). I am a specialist in plant nutritional science; I study mechanisms for the absorption of heavy metals by plants, as well as the functions and toxicity of these heavy metals in the plant's body. In this article, I will focus on cadmium and arsenic, which are toxic to both plants and humans.

2. Accumulation of cadmium in plants

Japanese people ingest about one-half of their cadmium from rice, with the remainder coming from other foods. Grains and vegetables take up dicationic cadmium dissolved in the soil solution. The cationic heavy metals that are taken up by plants include Fe2+, Zn2+, Cu2+ and Mn2+. A cation transporter that acts on uptake has been identified for each of these heavy metals, except for one specific to the uptake of Cd2+. The above-described dicationic transporter seems to take up Cd2+ incidentally

Cd2+ that was taken up by the root binds with anions, such as organic acids, at an apoblast site, and is transported to the xylem situated at the center of the root. Cd2+, which enters through a symplast site moves more slowly because it binds with glutathione, phytokeratin or metallothionein. Rice plants accumulated 90% of the absorbed cadmium in the roots. Cadmium that is transported up the xylem reaches foliage and fruits.

Approximately 1% of the cadmium that is taken up into rice plants is distributed to the fruit (i.e. rice grain). How does cadmium reach rice grains? Is it possible to suppress this migration into rice grains? These questions present interesting tasks for us to tackle. Cadmium has been thought to migrate directly to rice grains through the xylem, or is transported through the xylem to leaves and then to the rice grains through the phloem. Recent studies by the author and his team found that cadmium is transported through

the connected phloem, since rice grains are not connected to the xylem, and cadmium is not present in the form of free ions but was bound to

protein in the weakly alkaline fluid of the phloem. Since most of the cadmium that is transported from the root to the above-ground part through xylem is ultimately transferred to rice grains thorugh the phloem, my team estimated that cadmium in the xylem crosssed over to the phloem at a node. This xylem-to-phloem transport is found for other nutritional elements. When Cd2+ reaches the leaves, it is believed to bind to phytokeratin (PC) or metallothionein, and, in rice grains, to glutelin, a protein.

The suppression of the uptake of cadmium by the root and the migration to rice grains through the phloem may reduce the accumulation of cadmium in rice grains. Accumulation in leaf vegetables, on the other hand, may be reduced by limiting the availability of cadmium for the roots to take up and suppressing the transport of cadmium from the root through the xylem to the leaves.

Although certain plants that accumulate cadmium in a high concentration (hyperaccumulators) have been found in the areas of high cadmium concentrations, these plants are small in size. They can survive on cadmium-contaminated lands because they posses a system with which to detoxify the absorbed cadmium. It may be possible to clean up cadmium-contaminated soil by adding such a detoxification system to larger plants (phytoremediation).

3. Accumulation of arsenic by plants

People living in areas contaminated by arsenic take up arsenic mainly through drinking water, and a very little from food. Arsenic in fertilizers applied to the soil is absorbed into food and migrates to humans. In Bangladesh where the groundwater is contaminated by arsenic, drinking water as well as rice, wheat and vegetables grown with the irrigation of contaminated groundwater are reported to be contaminated by arsenic. Arsenic taken up by plants is anionic arsenic bound to oxygen as an arsenate (H3AsO4, H2AsO4-, HAsO42-). They are As(V) that resembles phosphates and arsenites (As(III)) in the form of the neutral As(OH)3. Anionic minerals taken up by plants include bromates (B(OH)4-), molybdates (MoO4-), as well as neutral mineral B(OH)3 and silicates specifically taken up by rice plant (Si(OH)4), which are respectively taken by anion transporters or aquaporin. Arsenates are taken by a phosphate transporter in the cell membranes of plants. Once inside the plant, As(V) is reduced to As(III) by arsenate reductase, and binds to phytokeratin containing a sulfhydryl (SH) group or glutathione (AS(III)-thiol aggregate) to be detoxified. Since the arsenates remaining as As(V) are analogous to phosphorus, they inhibit the production of adenosine triphosphate (ATP).

Reduction of the accumulation of arsenic in rice grains and vegetables can be achieved by suppressing the uptake by the roots of arsenic and reducing the transport rate of the absorbed arsenic to the parts above ground.

A recent study reported the discovery of a pteridophyte (Pteris cretica) that accumulates arsenic at a high concentration (Ma et al., 2001).

4. Human intake of cadmium and arsenic

Cadmium in food is bound to organic matter. It migrates to rice grains by binding to a metallothionein-like protein with a high cystine content. In albumen, cadmium is bound to protein. Kitagishi et al. reported a bond with gluterin (1976). Kitagishi is a pioneer in Japan in analysis of heavy metals in crops. Cadmium binds to citric acid in roots and accumulates in leaves, where it binds to phytokeratin, a compound that contains SH, and then accumulates in vacuoles within cells. We ingest cadmium bound to proteins or phytokeratin, which is likely absorbed as cadmium ions by the intestines. The absorption rate of cadmium in food is thought to be 2 to 8%, which is about one-tenth of the absorption rates of iron (60%) and zinc (75%) in food. A recent study by Horiguchi et al. (2004) reported that the cadmium absorption rate was correlated to age. The rates were 44% for those aged 20 to 30 years old, 1% for 40 to 59 years old and -5.9% for 60 to 79 years old, with an average of 6.5% for all age groups.

Arsenic exists in food as an aggregate with phytokeratin and inorganic arsenates, and as arsenate (As(V)) and arsenites (As(III)) in drinking water. Humans take in arsenic in these forms. It has been reported that pigs take up about 80% of arsenic contained in rice(Naidu, 2006).

Introduction

With the introduction of a risk analysis into the administration of food safety, Japan must promote a science-based administrative style. The Agreement on the Application of Sanitary and Phytosanitary Measures of the World Trade Organization (WTO) requires the member countries to base their domestic risk management measures on scientific principles and international standards. In response to these circumstances, the Ministry of Agriculture, Forestry and Fisheries (the "MAFF") formulated the standard work procedures for risk management relating to food safety1) to steer the approach taken by the ministry.

Prompted by damage to health (by cadmium) and the inhibited crop growth (by arsenic or copper) in some areas that are highly contaminated by mine effluent, the Japanese government implemented remedial measures to combat heavy metal contamination such as cadmium. In addition, the Japanese government is well aware of international trends, including discussions at the Codex Alimentarius Commission (the "Codex"), established jointly by FAO and WHO for the development of international standards for food, and making every effort from the perspective of maintaining food safety, including conducing surveys of heavy metal content in crops, establishing and diffusing technologies for the suppression of cadmium uptake by crops, and, risk communication.

Status of the Codex Alimentarius (Risk management of contaminants)

The Codex Committee has a committee for each field, in which the Codex Committee on Contaminants in Foods (CCCF) has jurisdiction over toxic substances, such as contaminants like heavy metals, and mold that might be unintentionally introduced into food during production processesNote. The contaminant-related Risk assessments regarding the contaminants are under the jurisdiction of the Joint Expert Committee on Food Additives (JECFA) of FAO and WHO, consisting of specialists in toxicological properties. The JECFA conducts toxicological assessments of contaminants and an evaluation of the intake from food based on requests from the Codex.

While the Codex is well known for their authority to establish international standards for contaminants in foods, they also focus on the prevention and reduction of contaminations throughout the course of crop production and the processing of foods so as to lessen risks the contaminants pose. Accordingly, the Codex developed the codes of practice for producers and processors of various contaminants to observe. While the establishment of the standards and the effects of eliminating non-compliant products from the market will primarily target the foods that contain a high concentration of contaminants, the implementation of proper technologies for reducing contaminants in the production or manufacturing processes will reduce the concentrations of contaminants in the regulated products in the market, and can ultimately achieve overall reduction in the distribution of intake of contaminants.

In addition to cadmium, which will be discussed later in this article, the Codex has investigated other environmental contaminants including lead, arsenic, dioxins and methyl mercury. The Code of Practice for the Prevention and Reduction of Lead Contamination in Foods has been established for lead, and standards have been set for concentrations of lead in agricultural, livestock and marine products. The Codex established the code of practice in respect of dioxins, but based on the recognition that the reduction of the concentration level in the environment at source would be more effective for the time and cost required by analysis, the Codex suspended the discussion on the standards. Although the JECFA sets a provisional allowable limit for the intake of highly toxic inorganic arsenic, their development work has been suspended since 1999 because the scientific morphology and morphological toxicity of arsenic in foods have yet to be elucidated, and there was no established analytical method for each form that arsenic takes in the body.

(Discussion on a standard for cadmium)

The Codex has been engaged in discussions of international standards for cadmium in foods based on the preliminary standards proposed at the 30th CCFAC meeting in 1998. In July 2005, the Codex adopted new standards for wheat and vegetables. The standards for polished rice and mollusks (e.g. saltwater bivalves and cephalopods) followed in July 2006. The 1998 draft preliminary standards included cereals, vegetables, fruits, meats (including internal organs), mollusks and crustaceans. Further discussions ensued based on the risk assessed by the JECFA, and the Codex discontinued discussions on food groups that were considered to have a lesser need for standards, taking into consideration regional contributions to cadmium intake. The standards that remained have also been modified according to actual cadmium concentrations.

Now, how will the Codex set the standards for contaminants, such as cadmium, which might be unknowingly contained in foods? The Codex General Standard of Contaminants and Toxins in Food (GSCTF) stipulates the following key principles:

1. Only for those contaminants that present both a significant risk to health and a known or expected problem in international trade;
2. Only for those foods that are significant for the total exposure of the consumer to the contaminant;
3. According to the ALARA (As Low As Reasonably Achievable) principle.

The ALARA principle requires regulatory agencies to set the standard to the lowest possible limit to the extent reasonably achievable. Specifically, it sets the limits for contaminants in foods to a level that is slightly higher than the normal range of concentration, so as to avoid the unnecessary interruption of production or trade, on the premise that the health of consumers is protected, and that uncontaminated foods are produced by the application of appropriate technologies and measures.

The international standard for rice, the staple food for the Japanese, was 0.2 mg/kg in its original draft proposal of 1998. As the result of Japan's proposal based on various surveys of actual cadmium concentrations in rice and stochastic evaluation of intake2) based on the surveys, the standard was revised to 0.4 mg/kg during the discussion process. The revision of the proposal was followed by the estimation by the JECFA of what impact the enforcement of these standards for various foods, including rice, might have on cadmium intake for each of the consumption forms over the world. Finally the Codex reviewed the results and adopted them as the standards based on the consideration of the results.

Japan's approach (Measures against cadmium)

Japan experienced serious social problems arising from the adverse effects on the health of the residents who live in the areas severely contaminated by cadmium from mine effluent as a result of consuming water and rice grown in their own paddy fields. These problems prompted the government to restrict the distribution of rice under the Food Sanitation Act, and implement soil remediation projects under the Agricultural Land Soil Pollution Prevention Act.

At the same time, the government realized that the effect of cadmium on human health on which the Codex based its standards was intended to describe the health risk of ingesting food with the lower concentration than the above; a provisional allowable intake guideline was set by JECFA with a cadmium intake that would pose no health risk even if a person continued to ingest this amount for life. The limit was 7 μg per 1 kg of body weight per week.

According to annual surveys on the intake of contaminants, which the MHLW has conducted since 1977, in 2004, a typical Japanese ingested an average 20 μg per day of cadmium from daily food, which was about 40% of the allowable intake set by the JECFA for a 50-kg person. Also, rice was the largest source of cadmium intake, accounting for one-half of the entire intake3).

Based on these results, the MAFF began surveys of (concentration distribution) actual cadmium concentrations in mainly rice (approximately 37,000 rice samples) and other domestic agricultural and livestock products produced. The Ministry is currently developing and diffusing technologies for the reduction of risk at source during the production phase of the agricultural products. A technique of flooding the paddy fields around the time of heading of the rice, which provided the largest contribution to cadmium intake, to maintain moisture in the soil and absorb cadmium, has been found to reduce cadmium concentrations in rice. Farmers in the areas that might have the potential to produce rice with a high concentration are being actively encouraged to adopt this technique.

The water control method for paddy fields was implemented in 2004 in areas covering a total of 30,000 hectares, and more than 40,000 hectares in 20064). A comparison with the fact that the areas highly contaminated by cadmium for which the soil dressing projects have been implemented over three decades since the 1970s covered 6,000 hectares5) illustrates the scale of the project. Unlike engineering measures such as soil dressing, the effectiveness of the water control, a farming practice, is dictated by the weather conditions in that year. Yet, it is believed to be sufficiently effective in reducing the long-term intake of cadmium by consumers. A calculation of changes in the cadmium intake from food using data of the areas, where more than 0.4 mg/kg of cadmium was detected in the past from ongoing monitoring surveys by the MAFF, indicates declining trends since 2004. The MAFF is also involved in the development of technologies for the suppression of cadmium absorption by crops other than rice, phytoremediation, and soil cleansing.

(Surveys on arsenic intake)

The MAFF is in the process of compiling a priority list of toxic chemical substances to be controlled for risk management in order for the Ministry to be able to conduct systematic surveys on the status of these substances in foods7), based on the information on food safety and the opinions of consumers and food industry sources.

The priority list includes environmental contaminants such as arsenic, cadmium, methyl mercury, dioxins and lead. For arsenic, lead and mercury, national surveys of domestically-grown agricultural products began in 2003 under a 4-year plan to collect basic data for discussions as to the need for future risk management measures. The overall results of these surveys are currently being compiled. According to the 2-year interim report, provisional calculations of the average intake by consumers from agricultural products indicate several conclusions8):

1. Lead is less than 10% of the provisional allowable weekly intake set by the JECFA;
2. Total arsenic intake is about 30% of the provisional allowable intake of inorganic arsenic assessed by the JECFA; and
3. Total mercury is less than 10% of the allowable weekly intake of methyl mercury assessed by the Food Safety Committee for pregnant women.

As the concentration of arsenic in rice is higher than in other agricultural products, and the contribution of rice to intake is large, an analysis is being conducted on inorganic arsenic for which the provisional allowable intake has been set. In addition, studies and factual surveys regarding the analytical methods for arsenic in marine products in various forms are underway as these products are likely to be a large contributor to arsenic intake in Japan.

Food products are not significant contributors of dioxins. The baseline concentrations have been determined by national surveys during the period from 1999 to 2002. The baselines are used as a guideline for determining the effects of dioxins on agricultural products when environmental pollution occurs near agricultural lands. The MAFF is conducting a survey at the moment so as to determine whether yearly changes in the dioxin concentrations can be observed as a result of measures to control discharge of dioxins.

Conclusion

As stated at the beginning, Japan has just adopted the approach of risk analysis in the administration of food safety. For cadmium, the Pharmaceutical and Food Sanitation Council deliberates revisions to the domestic standards as soon as the results of current health risk assessment by the Food Safety Committee are announced. The Ministry must communicate the risks to consumers, producers and other stakeholders during the development of national measures for risk management. Although the MAFF is organizing discussion meetings in collaboration with the MHLW and disseminating information through the web sites of the ministries, it is essential that the information is scientific and appropriate (the probability and extent of adverse impacts on health) in regards to approaches that producers will implement with respect to risks if the communication is to be successful with all who are involved.

It is also important to implement the so-called food chain approach in the effort to secure the safety of foods. This approach not only controls the final products but also secures safety of foods through all stages from primary production to consumption. The MAFF expects to achieve this objective by developing a code of practice and a new framework, which will incorporate measures for the production processes in the Good Agricultural Practice technique (GAP) so as to promote them to the producers. In future, the MAFF plans to establish measures to control cadmium, such as the water control scheme, to be implemented at production fields through these frameworks.

As for arsenic, we are in the early stage of development of a risk management program. In conjunction with the current effort to determine the actual concentration levels in agricultural products, we must collect a wide range of scientific information, including data on toxicity to humans, and morphological changes and behavior of arsenic in soil and other production environments as well as in agricultural products.

1. Ministry of Agriculture, Forestry and Fisheries and Ministry of Health, Labor and Welfare (August, 2005), On Development of the Standard Procedures for Risk Management of Food Safety by Ministry of Agriculture, Forestry and Fisheries and Ministry of Health, Labor and Welfare.
2. Hiroshi Nitta (November, 2003), Study of Estimation of the Exposure to Cadmium by Japanese - The 2003 Interim Analysis Report
3. Ministry of Health, Labor and Welfare (August, 2006), Q & A on Cadmium in Foods
4. Ministry of Agriculture, Forestry and Fisheries (May, 2007), The 2007 Action Plan for Measures Against Cadmium in Foods
5. Ministry of the Environment (December, 2006), Status of the Application of the Agricultural Land Pollution Prevention Act in 2005
6. Ministry of Agriculture, Forestry and Fisheries (July, 2007), Evaluation Results of the Agriculture, Forest and Fisheries Policy (Evaluation results of the measures implemented in 2006).
7. Ministry of Agriculture, Forestry and Fisheries (April, 2006), Mid-term Plan for Surveillance/Monitoring of Toxic Chemicals for Food Safety.
8. Ministry of Agriculture, Forestry and Fisheries (March, 2006), Interim Reports on Actual Contents of Lead, Arsenic and Mercury in Domestic Agricultural Products.

l. Biological effects of cadmium

One of the best known pollution diseases as the biological effects of cadmium (Cd) is the "itai-itai disease" which presents renal dysfunction and impairment of bone metabolism as a result of chronic exposure to cadmium. Reported biological effects resulting from acute and chronic cadmium poisoning at industrial work sites include pulmonary edema, metal fume fever, bronchitis, pulmonary emphysema and renal dysfunction. There have been reports, including the results of animal tests, that link cadmium to reproductive, urinary and cardiovascular diseases and diabetes, as well as potential carcinogenicity and endocrine disturbances (ICPS, 1992; Nogawa et al., 1999; Goyer, 1997).

The effects of chronic exposure to cadmium on renal function and bone metabolism are generally believed to be the onset of renal dysfunction followed by impaired bone metabolism. Problems appear to lie in the interpretation of indicators used for the assessment of renal dysfunction, and the determination of impaired bone metabolism in terms of osteoporosis and osteomalacia, as well as the relationship with the onset of these illnesses. The mechanisms for the transmission of cadmium through human cell membranes (i.e. a transport mechanism), the onset of renal dysfunction, and impairment of bone metabolism have yet to be elucidated in detail (ICPA, 1992; Nogawa et al., 1999; Goyer, 1997; Ohta, 2001; Ohta et al., 2000).

II. Issues relating to cadmium intake

There are some areas in Japan where a relatively high concentration of cadmium in agricultural products presents health concerns via exposure to cadmium through foods. These areas are the subject of ongoing epidemiological studies.

As rice is the staple food for the Japanese, an allowable intake level for cadmium in rice must be examined and established based on the dose-effect relationship of cadmium in the human body.

At present, the Food Sanitation Act prescribes 1.0 ppm to be the standard limit for cadmium concentration in rice in Japan. Distribution of unpolished rice that contains more than 0.4 ppm is prohibited. A standard of 0.2 ppm was proposed to the Codex Alimentarius Commission (the Codex), a joint international standards setting organization of FAO and WHO. The current standard in Japan is 0.4 ppm. Is the 0.2-ppm standard proposed by the Codex reasonable? Are there sufficient grounds for that standard? When it comes to the indicators for health assessment and significance levels and criteria for standards, a consensus has yet to be reached. The JECFA (the Joint Expert Committee on Food Additives of FAO/WHO) has set the provisional tolerable weekly intake (PTWI) at 7μg/kg/week. Further experimental work for the assessment of biological effects of daily cadmium intake and the accumulation of epidemiological survey data are essential for risk assessment.

III. Issues relating to assessments of biological effects of cadmium

With respect to experimental work for an assessment of the biological effects of cadmium, there is a considerable pool of data accumulated from various experiments that used means such as injections of relatively large doses for the purpose of problem-solving or surgical means to elucidate the involvement of biological functions. There have been experimental studies using a prolonged administration of cadmium to test subjects through water or feed. However, few have investigated intestinal absorption in or assessment of biological effects of long-term exposure to cadmium by humans through daily intake. In particular, there has been no detailed examination of the effects of exposure to cadmium that take into consideration the normal physiological loads (pregnancy, childbirth and nursing) on female animals. There have been few detailed investigations into the modification of chemical forms during intestinal absorption and involving in vivo distribution and biological effects of cadmium.

Based on the results of the assessment of the biological effects of acute and subacute cadmium poisoning caused by usual environmental contamination or workplace exposure, the assessment of biological effects of cadmium at a daily intake level may be limited. In other words, the lower the concentration of cadmium is at exposure, the more affected is the modification of the biological effects of cadmium by the presence of metallothionein (MT), a metal-bound protein in intestinal tissues, modification of chemical form of cadmium derived by MT, and accompanying changes in biodistribution and the interaction of co-existing nutrient factors.

We need to conduct more detailed investigations into cadmium in terms of determining its intestinal absorption rate, developing proper assessment indicators for intake and accumulation, examining the load-modifying effects of pregnancy on female animals, mother-child transmission and effects of reproductive toxicity.

These investigations need to assess the biological effects of cadmium at the level of daily intake, and this is an important and current issue with respect to setting a tolerable intake (ICPS, 1992; Ohta, 2001; Ohta, H. et al., 2000; Ohta & Cherian, 1991; Rogers et al., 1997; Kovacs & Kronenberg, 1997; Brzoska et al, 1998; Bhattacharyya et al., 2000; Ohta et al., 2006)

IV. Attempt at an extrapolation of animal studies to humans and an estimation of tolerable intake

The results of an examination of renal function and bone metabolism of female rats orally administered with fixed doses of cadmium (2"60mgCd/kg/day) showed that the onset of impairment of renal function and bone metabolism varied according to the conditions of cadmium exposure, suggesting that the impairment of bone metabolism was not an event secondary to the renal dysfunction but rather a direct effect of cadmium on bone metabolism. Based on this result, the relationship between the concentration of cadmium in kidneys relative to the dose in an animal study (Ohta et al., 2000) and the concentration of cadmium in renal cortex obtained by a study of clinical epidemiology on humans was examined, and an oral dose of cadmium with consideration given to the extrapolation to humans (Fig. 1) to examine the effects of reproductive loads and cadmium exposure on mothers. The bone metabolism of the mother showed a significant decrease in the density of femur owing to the effect of cadmium exposure in addition to nursing load. On the other hand, no significant differences were observed between the experimental group administered with cadmium in a dose equal to the estimated daily intake of humans and a control group (Fig. 2). The experimental group administered with cadmium at a dose twice the daily intake (7"8μg/kg /day) showed significant loss in bone density, suggesting that the setting of a tolerable intake level of cadmium would need to take nursing load into consideration. The concentration of cadmium in the kidneys did not show any significant effects of pregnancy/nursing loads in this experiment with excretion of amino acids, NAG and β2MG into urine increasing significantly at 20 40 μg/g. This was an extremely low level of concentration compared to the conventional critical renal cadmium concentration of 200 μg/g.

With respect to this experiment, the author will present to the symposium the outcome of an attempt to estimate the tolerable daily intake of cadmium for humans based on the changes in various indicators for the assessment of abnormal renal function and bone metabolism obtained from the experiment, with aid of computer software provided by the US Environmental Protection Agency for the calculation of a benchmark dose (BMD).

V. Conclusion

As the biological effects of exposure to cadmium at a relatively high concentration in an industrial workplace or in a contaminated environment have sharply declined, the new question is how we should assess the biological effects of cadmium intake in our daily life. Is there an accumulation of study results sufficient to contribute to the setting of a tolerable intake standard for cadmium? Is the Japanese standard for cadmium reasonable in comparison with the results reported by studies overseas? Is it appropriate to assess the risk of an adverse effect of daily cadmium intake on health from the research results at a level of conventional environmental contamination? The issue is how and at what level should the indicators for adverse health effects of cadmium be set. There should be studies that are cognizant of more realistic junctions between experimental work using cells and animals and epidemiological studies using humans.

The standards for food distributed in world trade are set by the Codex Alimentarius Commission (the Codex). The Codex reports to the Joint Expert Committee on Food Additives (JECFA), a joint organization established by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). The JECFA is a group of experts who determine the total allowable intake for food additives and the tolerable intake for contaminants through foods and beverages. Based on the decision of the JECFA, the Codex Committee for Contaminants and Food Additives (CCFAC) sets the allowable concentration and tolerable concentration of a substance in each food item. The CCFAC is a subordinate body of the Codex. I attended six JECFA meetings: the 55th meeting in 2000, the 57th in 2001, the 61st in 2003, the 63rd in 2004, the 64th in 2005 and the 66th in 2006, as well as the related meetings: Codex Alimentalius meeting in 2002 and Committee for Contaminants and Food Additives (CCFAC) in 2003, as a technical adviser to the Government of Japan. Drawing from my experience, I would like to discuss the strategies of the US and EU for food safety and world food trade that emerged from these meetings.

The subject of this discussion is the contaminants that Japanese people ingest at high doses because of their love of food that contains these contaminants, as well as the contaminants in foods that are favorites of Asians but not popular among westerners. They are cadmium, methyl mercury, and chloropropanol.

At the 57th JECFA meeting, the spotlight was on the carcinogenicity of two of the chloropronanols, namely, 3-chloro-1,2-propnanediol and 1,3-dichloro-2-propanol (the "chloropropanols") which were generated as impurities during the acid decomposition of plant protein. Most of the intake from food sources comes from soy sauce. However, the concentration in soy sauce made by the traditional fermentation method in Japan should not create any problem, as this traditional method generates very little of those two substances. On the other hand, there may be some impact on Japanese producers of flavor seasonings. Producers of oyster sauces in China, Southeast Asian countries and Korea may be required to change their manufacturing method, which may create a serious economic hardship.

Assessment reports of 3-chloro-1,2-propanediol and, 3-dichloro-2-propanol can be found in papers published in the 1980s, but the studies were never on a large scale. The document that turned out to be the most important for assessment was not a published paper but a report prepared by Nestle. Study reports of a laboratory with Good Laboratory Practice are acceptable as assessment documents even if they have never been published. In spite of the fact that the Nestle report assessed the lowest dose as NOEL, the assessment by the Drafting Group of the JECFA produced a provisional maximum tolerable daily intake (PMTDI) that was lower than the Nestle's dose. The group assessed the minimum dose as LOEL and then multiplied it by a high safety factor. By the way, the JECFA Drafting Group consisted of Switzerland, the Netherlands and the United States.

This development suggested that the Drafting Group interpreted the study results to suit their agenda. These standards are not scientifically sound. Behind all this was the decision of EU standards on the same substances that was made public one week earlier. The intention of the EU representatives was apparently to harmonize the JEFCA standards with the EU standards. There is another point: this harmonization would be beneficial to Nestle. The company owns established processing techniques that use enzymes. They have commercial products out in the market place. The low standard might further freeze Asian flavor seasonings out of their markets.

During the meeting, the participants from Japan and Thailand pointed out that the assessment was scientifically wrong. Dr. Shubik of UK also pointed out errors in the argument. Yet, the opinion of a WHO committee member, who had the authority to rule, steered the argument toward the adoption of a 0 to 2 μg/kg body weight as PMTDI, as originally proposed by the Drafting Group.

The 66th meeting held in Rome in June 2006 discussed the draft proposal recommending that the PMTDI should be halved because study reports indicated that these substances might trigger adverse effects on the spermatogenesis of male rats born after in utero exposure. In the second week of the meeting, however, the reliability of the data analysis in that report was questioned, and the report was rejected. In the end, the current PMTDI was upheld. Although this deviates from the discussion about determining tolerable intake, our argument at the meeting was that "shoyu" made by the traditional fermentation method that contains little or no chloropropanols was the soy sauce to the Japanese people, and therefore, the term "soy sauce" should not be used in a Codex document. The discussions at the Codex meetings in the past indicated that we have had no chance of winning the argument. In the end, we concluded by having a category of "soy sauce containing protein that breaks down the subject acids" inserted in the beginning of the document.

The assessments of cadmium, dioxins and methyl mercury must also go through the process and steps unique to the JECFA, which are somewhat incomprehensible to first-time committee participants. Yet, some items such as the determination of safety and uncertainty factors are very difficult to understand by reading the assessment documents unless you attend the meeting in person to hear the discussion. I will explain the processes of the Codex assessment so you will understand how international standards are developed and adopted. As the standards are moving toward stricter levels, those who are involved in the standard setting should have a good grasp of the flow of the decision-making process.

In the background, there is an increasing demand on producer countries to set allowable standards at the lowest possible level according to the ALARA principle (As low as reasonably achievable), the Good Agricultural Practice (GAP) and the Good Manufacturing Practice (GMP) for the sake of keeping food safe. There are, however, large differences among the world's food cultures. There will be no objection to setting very strict standards for rice or soy sauce if such strictness has no impact on the food culture to which the committee members belong. The standards set by the JECFA will become the basis for the Codex standards. To the affected countries, the standards may create serious problems in their agriculture and trade.

The JECFA meetings are a battleground for scientific knowledge and logic for risk assessment experts. Attendees are required to participate and engage in discussions as individual researchers, not representatives selected by their government. You cannot deny the strong influences of the values based on your country and culture, particularly, the food culture. The JECFA meetings are a series of battles of scientific arguments complicated by an assortment of factors. Submission of documents, information and measurement data relating to assessments by the JECFA and the Codex in order for Japan to regularly send an army of experts to their meetings will be an international contribution that plays a pivotal role. Our participation in the past, however, was in the capacity of individual scientist without the support to wage a personal battle in the JECFA arena. Lack of preparation was a serious detriment. The United States often takes charge of developing the first draft. They start the preparation as early as three months before the meeting, and use several post-doc researchers working on each substance. The biggest contribution from Japan was standards for cadmium. A vast collection of screening data on cadmium concentration in rice by the MAFF was powerful ammunition. We must be well-prepared and vigilant in future so that we would not be put at a disadvantage in issues relating to food. The Japanese Government should be always prepared for the JECFA and the Codex.

Introduction

Impairment of health caused by heavy metals is an important issue in the filed of clinical ecology. In the United States, the American Academy of Environmental Medicine gives a high priority to the study of heavy metal poisoning, such as toxic metal syndrome (H.R. Casdorph and M. Walker) and chemical brain injury (K. H. Kilburn). The risk of health impairment due to exposure to heavy metals stretches wide covering fetuses to adults. The questions include fetal exposure through the mother's body, a possible linkage between exposure during the natal developmental stage of the central nervous system (the brain, in particular) and autism or attention deficit-hyperactive disorder (ADHD), and the generation of malignant tumors by chronic poisoning.

My presentation is entitled the "Heavy Metal Problems From the Perspective of Clinical Ecology"; I will overview the recent trends in heavy metal problems, and shed light on the problems of mainly arsenic exposure from the perspective of clinical ecology.

Background

Owing to the improvements in the environment for living and working in Japan and other advanced countries, we have less chance of being exposed to arsenic, and health problems are on a lesser scale compared to the past. From a global perspective, however, the risk of exposure to minute amount of arsenic still exists. Chronic arsenic poisoning induces disorders of the skin and peripheral nerve system, mental impairment, and hematopoietic disorder. In addition, arsenic is known to cause malignant tumors of the skin and internal organs (e.g. lung cancer, hepatic angiosarcoma, bladder cancer). Chronic arsenic poisoning caused by the contamination of well water by inorganic arsenic is well known, with incidences reported from many Asian regions, including China, India, Bangladesh and Thailand, as well as in South and Central America, including Mexico, Chile and Argentina.

Man's long relationship with arsenic

Our relationship with arsenic dates back to ancient Greece where arsenic was used as a medicine. Arsenic was also prized as a magic potion for eternal youth. Even today, a Chinese herbal medicine "xiong huang" is widely available at herbal medicine shops across China as an anti-inflammatory and antitoxic drug. Arsenic was also used in modern medicine from the 19th century to early 20th century, such as in Fowler's Solution. It was a panacea that cured scabies, syphilis, rheumatism and even cancer. One of the best sellers was arsphenamine developed by Hata and Ehrlich (commercial name: Salvarsan). The Ministry of Health, Labor and Welfare approved pasta arsenite (commercial name: Neoarsen Black) as a pulp devitalizer in dentistry, and a 0.1% arsenite solution for the treatment of leukemia in 2004. The latter is used for recurrent or intractable acute myelogenic leukemia. Outside medicine, arsenic is used in CCA (chromium, copper and arsenic) for the preservation of building foundations as well as in ant repellants as arsenite, Arsenic was also used as fertilizer until 1998. Arsenic sulfide is used as an additive to firecrackers.

Arsenic exists close to humans in a variety of things in our life, used as raw material for compound semiconductors, or additive to sheet glass to increase transparency. As food and drink, seaweed hijiki (hondawara family) contains a high concentration of inorganic arsenic. Wakame, kelp and nori also contain arsenic, but not much inorganic arsenic. Organic arsenic is more prevalent in fish and shellfish. The reader should be warned that some drinkable hot spring waters contain a high concentration of inorganic arsenic

Arsenic poisoning

In what circumstances does arsenic poisoning occur in everyday life or at work? The most infamous food poisoning case was the Morinaga Arsenic Milk Case (1955). About 12,000 infants suffered subacute poisoning by arsenic that was accidentally mixed into milk stabilizer used in baby formula. More than 130 reportedly died as a result. Many victims still suffer from central nervous system disorders as an aftereffect. Air pollution was the culprit for arsenic poisoning in areas surrounding Toroku Mine and Sasagaya Mine, as well as cases in Quizhou province of China where coal fuel was the source. Arsenic causes serious occupational hazards in the workplace in the form of smelter fumes, dust from glass and the semiconductor industry. Areas of noteworthy environmental (natural) arsenic poisoning cases include China, Bangladesh, India, Thailand, Mexico, Chile and Agentina. The poisoning occurred from drinking contaminated water. A man-made environmental exposure to arsenic caused by an organic arsenic (containing diphenyl arsine) occurred in 2003 in the town (now city) of Kamisu in Ibaraki prefecture.

Mechanism of onset of arsenic poisoning

As described above, the chronic effects of arsenic have been known from human cases of chronic exposure to arsenic as well as through epidemiological surveys. There have been, however, many unknown factors regarding the mechanism of the onset of symptoms. Mechanisms suggested as possible in the human body include the methylation and oxygen reduction of exposed inorganic arsenic that changes chemical forms rapidly. Establishing experimental animal species suitable for arsenic study is difficult, as metabolic rates vary widely from species to specie; also, in vitro experiments do not sufficiently reflect the biological effects.

It has been believed that humans reduced the toxicity of arsenic by methylating acutely toxic inorganic arsenic and eliminating it in urine, thus avoiding the impairment of health. Now we know methylated arsenic has a stronger involvement in carcinogenesis. In addition to carcinogenesis, some data suggest that methylated arsenic might be one of the culprits for benign skin symptoms by chronic exposure to inorganic arsenic. Furthermore, it is very important to know that loci of expression of symptoms differ according to the path of arsenic exposure. Occupational exposure leading to most cases of respiratory absorption is strongly linked to lung cancer, but if arsenic was absorbed through the digestive system, lung cancer is rare.

Biological reactions to arsenic are extremely complex. It will take considerable time to unravel the mystery completely. Yet arsenic poisoning by chronic exposure and trace arsenic contamination in ordinary environments are occurring globally right now. We must recognize that this is an urgent health issue.