COOPERATIVE EXTENSION UNIVERSITY OF CALIFORNIAEXTENSION TOXICOLOGY NEWSLETTER

The last two issues of the Environmental Toxicology Newsletter have focussed on food safety issues. This issue is a "catch-up" issue on other items of interest that have been delayed in presentation, but are important pieces of the modern toxicology puzzle. These articles are presented to offer some perspective on current areas of human toxicology and health. They contain some technical jargon which is defined in italics in parenthesis immediately following the "ten dollar" words.

The dioxin article is quite interesting because it demonstrates that human exposure to large doses of dioxin results in relatively few measurable effects, even after a very high dose exposure. Thirteen years have passed since the incident in Seveso, and so far, only acute toxic effects were noted in the exposed population. The next five to ten years will help to complete the story, and it is especially valuable that there is data about the levels of dioxin in the exposed population.

The article about the differences in congenital malformations (birth defects) in U.S. minority groups is especially interesting, and points out the difficulty in trying to pinpoint why such differences exist. So far it is impossible to sort out all of the genetic and environmental (for example, lifestyle) factors which would contribute to the observed differences, alcohol and tobacco consumption being two exceptions to this.

The article about endrin poisoning was of particular interest to me because it is the first case reported in the United States. The poisoning was not diagnosed in one of the patients, and his convulsions were attributed to epilepsy, resulting in a legal hearing over his eligibility to continue to drive.

The report on lead poisoning is included because lead continues to be a problem in many ways. More than ten years ago there was a report of a family in New Mexico (one of whom was a physician) who were poisoned in exactly the same way as reported here. Of particular note is the fact that previously safe pottery can become unsafe if the glazes become chipped or deteriorate.

The last article on dolphin deaths in the Atlantic Ocean is also of interest to me because when I was in Germany last year, there was a dolphin kill in the North Sea, which at first was thought to be due to pollution, and which ultimately was shown to be due to natural toxicants as well. There are many natural toxicants under the sun, and they must be kept in mind whenever unexplained deaths occur.

II.Preliminary Report: 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure to Humans -- Seveso, Italy

At approximately noon on Saturday, July 10, 1976, an explosion occurred during the production of 2,4,5-trichlorophenol in a factory in Meda, about 25 km north of Milan, in the Lombardia region of Italy. A cloud of toxic material was released and included 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Debris from this cloud fell south-southeast of the plant on an area of about 2.8 km2 (700 acres), including parts of the towns of Seveso, Meda, Cesano Maderno, and Desio. The size of the contaminated area was estimated primarily by measuring TCDD in the soil; additional criteria included the presence of dead animals (e.g., birds, rabbits, chickens) and detection of dermal lesions among persons in the area. The contaminated area was divided into three zones (A, B, and R) depending on the concentration of TCDD in the soil (Table 1). An additional zone, Zone S, outside the contaminated area was examined as a control zone.* Zone A, the most heavily contaminated section, was further divided into seven subzones, A1-A7, based on increasing distance from the factory. The total amount of TCDD deposited in the contaminated area was initially estimated at about 165 g; subsequently, it has been estimated to be at least 1.3 kg.

* Zone R was originally thought to be a reference zone, but on subsequent detection of TCDD concentrations in soil, Zone S was added.

Size		Soil sampling		TCDD concentration (lg/m2)
Zone	Population	(acres)	square (m2)	Mean	Highest
A	735	198	2,500	230.0	5477.0
b	4,699	665	22,500	3.0	43.9
R	31,800	3,532	22,500	0.9	9.7

* These data may be underestimated by approximately 25%. >Measured in a soil sample, 20 cm of depth, taken at the center of a square.

Within 20 days of the explosion, the Italian authorities had evacuated the 211 families (735 persons) from the area later defined as Zone A and had taken immediate measures to minimize the risk of exposure to residents in nearby areas (primarily those in Zone B). The Italian authorities were assisted by several national and international technical commissions in assessing adverse health effects. Residents of zones A, B, and R underwent extensive medical examinations from 1976 to 1985; chloracne (chlorinated hydrocarbon induced acne, similar to common acne in appearance, but causally related to chemical exposure), detected in a small segment of the population, was the only abnormal finding. Only one potentially exposed person was measured for TCDD; she was a 55-year-old woman residing in a portion of Zone A (mean TCDD soil concentration of 185.4 lg/m2), who died from pancreatic adenocarcinoma 7 months after the explosion. Her TCDD whole-weight levels varied from 6 parts per trillion (ppt) in blood to 1840 ppt in adipose tissue. ( Levels of TCDD in serum or adipose tissue of the general population are <20 ppt.)

In April 1988, a group of U.S. and Italian scientists convened to further examine the Seveso TCDD incident. Since more than 30,000 serum or plasma samples (volumes of 1-3 mL) had been collected from residents of the four zones from the end of July 1976 through 1985 and stored at -30 C (-22 F), the group agreed to assess whether methodology developed at CDC to measure TCDD in human serum could be used to measure TCDD in these low-volume samples. This methodology, a lipid-based measurement highly correlated with paired measurements of TCDD in adipose tissue (p= 0.98), has been used to evaluate U.S. Army veterans, U.S. Air Force Operation Ranch Hand veterans, and occupationally exposed persons (D.G. Patterson, Jr., et al., unpublished data).

The preliminary Seveso study evaluated serum samples from five Zone A residents who developed the most severe types (III or IV) of chloracne; four Zone A residents who did not develop chloracne or other health problems (in 1976, each was > 15 years of age); and five persons from Zone S. All these samples had been collected in 1976 and were sent without identification to CDC for analysis. These samples were analyzed for TCDD on both a whole-weight and a lipid basis, using triglycerides and total cholesterol data provided for those samples by the laboratory of the hospital of Desio-Milan to calculate total lipids.

The TCDD levels detected are the highest ever reported in humans (Figure 1). The three highest levels are from children who developed chloracne. Levels for the other two chloracne cases were similar to those in residents without chloracne. TCDD was not detected in four of the five controls. In one control, a level of 137 ppt TCDD on a lipid basis was detected; this value may represent either an actual level or the detection of a residue of < 1% from a sample analyzed immediately before this sample.

Reported by: P Mocarelli, MD, Institute of General Pathology, Univ of Milan and Hospital of Desio, Milan; F Pocchiari, PhD, Instituto Superiore di Sanita, Rome. N Nelson PhD, New York Univ Medical Center, New York, New York. Center for Environmental Health and Injury Control, CDC.

Editorial Note: Little is known about TCDD exposures and adverse health effects in humans. However, these Seveso samples are unique in that they were taken in proximity of time to an acute human exposure to TCDD. Thus, they and the subsequent samples allow for correlating TCDD levels and adverse health effects, if any, and for determining the half-life of TCDD in humans. This population has no apparent adverse health effects other than chloracne.

These serum measurements confirm overt exposure to TCDD in those persons tested who resided in Zone A. The levels are of the same magnitude as those found in occupational studies that estimate initial TCDD levels by extrapolating to the time of last exposure (by assuming first-order kinetics and a half-life of 7 years). Although the three highest TCDD serum levels occurred in persons who developed chloracne, no threshold level for chloracne is obvious.

FIGURE 1. Serum TCDD levels* of Zone A residents (with and without chloracne) and Zone S controls -- Seveso, Italy

* Levels of TCDD in serum or adipose tissue of the general population are < 20 ppt.

III. Leading Major Congenital Malformations Among Minority Groups in the United States, 1981-1986

Congenital malformations are a major cause of infant morbidity and mortality in the United States. In 1985, birth defects were the leading cause of infant mortality and the fifth leading cause of years of potential life lost. Birth defects contribute significantly to chronic disease morbidity (incidence of disease) and related medical costs. Approximately 30% of all admissions to pediatric hospitals are associated with birth defects, and expenditures for medical care have been estimated at $1.4 billion per year.

All populations share the burden of congenital malformations, although the frequency and types of malformations may vary by race, ethnicity, and socioeconomic status. Access to medical care, nutrition, maternal lifestyles, and education are considered to be important factors in the occurrence of neural tube defects (birth defects that occur early in development and affect the brain and spinal cord).

A large prospective study showed that blacks had higher overall rates of malformations than whites; this difference was primarily due to an increase in minor malformations such as polydactyly (extra digits), branchial clefts (during development, mammals have "gill arches" like fish, and if these do not close properly, clefts can occur), and supernumerary nipples (extra nipples), whereas whites had higher rates of major malformations and multiple malformations. Higher rates of neural tube defects were observed among infants of Hispanic women born in Puerto Rico and residing in Brooklyn than in their non-Hispanic black and white counterparts. American Indians appear to be at high risk for fetal alcohol syndrome. According to a recent study, the fetal alcohol syndrome (a well defined set of birth defects associated with maternal alcohol abuse) rates for American Indians of the southwestern United States range from 13 to 103 per 10,000 live births. These rates vary greatly by subpopulation group (tribe). Several factors, such as culture influences, fertility, patterns of alcohol consumption, nutrition, and metabolic differences, are believed to play an important role in the distribution and occurrence of fetal alcohol syndrome among American Indians. Furthermore, oral clefts (during development, the mouth parts are formed by the fusion of tissue from both sides, and if this does not occur, cleft palate and cleft lip may occur) and congenital heart anomalies reportedly occur more frequently among American Indians in British Columbia than in the general population.

An analysis of the 18 major birth defects by racial/ethnic group showed that American Indians had the highest total rate, followed by whites, blacks, Asians, and Hispanics, respectively. American Indians had the highest rates of hydrocephalus (water on the brain, caused by lack of a drain valve for spinal fluid) without spina bifida (incomplete closure of the spinal column, leaving the spinal cord exposed); atrial septal defect (holes in the walls of the heart); valve stenosis (narrowing) and atresia (absence of the opening); cleft palate without cleft lip; cleft lip with or without cleft palate; rectal atresia and stenosis; fetal alcohol syndrome; and autosomal abnormalities (too few or too many chromosomes), excluding Down syndrome. Rates for clubfoot without central nervous system (CNS) defects, hip dislocation without CNS defects, and hypospadias (opening of the urethra on the underside of the penis) were highest among whites. Rates for microcephalus (very small head), patent ductus arteriosus (The ductus arteriosus is a blood vessel which shunts blood around the lungs while the fetus is in the womb, and which should close almost immediately after the first breaths are taken. If it does not close, the baby is "blue" and often in need of surgical closure of the shunt), and pulmonary artery stenosis were highest among blacks. The highest rates of anencephaly (absence of brain tissue in the cranium), spina bifida without anencephaly, and Down syndrome occurred among Hispanics. The rates for two major birth defects--anencephaly and ventricular septal defect--were highest among Asians.

Among blacks, rates for six malformations were statistically significantly higher and rates for nine malformations were statistically significantly lower than rates among whites. Patent ductus arteriosus was the leading major congenital anomaly among blacks, possibly reflecting the high rate of prematurity in blacks. Patent ductus arteriosus occurred twice as frequently as hypospadias, the second leading major malformation among blacks. The fetal alcohol syndrome black:white rate ratio of 6.67 (Cl = 5.71-7.79) was noteworthy.

Among Hispanics, the rates of anencephaly, microcephalus, and Down syndrome were significantly higher than those among whites. Spina bifida without anencephaly was more prevalent among Hispanics, although the difference in rates was not statistically significant. Neural tube defects have been previously documented as being more prevalent among certain Hispanic subpopulations. The high rates of Down syndrome may be partially explained by advanced maternal age, inadequate access to medical care, or poor use of health services among Hispanics. On the other hand, rates for seven major congenital malformations were statistically significantly lower for Hispanics than for whites.

As among blacks, patent ductus arteriosus was the most prevalent congenital malformation among American Indians; it was followed by hip dislocation without CNS defects and fetal alcohol syndrome. The rate of fetal alcohol syndrome among American Indians was 29.9 per 10,000 total births, and the rate ratio was 33.22 (Cl = 25.08-44.00) compared with whites. Rates for other malformations were also statistically significantly higher for American Indians than for whites; these malformations were valve stenosis and atresia, hydrocephalus without spina bifida, cleft lip with or without cleft palate, and cleft palate without cleft lip. Rates for hypospadias and clubfoot without CNS defects were statistically significantly lower for American Indians than for whites.

Most prevalent among Asians were patent ductus arteriosus and hip dislocation without CNS defects. Rates for anencephaly, Down syndrome, cleft lip with or without cleft palate, and ventricular septal defect tended to be statistically significantly higher among Asians than among whites. Rates for hip dislocation without CNS defects, hypospadias, and clubfoot without CNS defects were statistically significantly lower among Asians than among whites.

The overall distribution of the leading major congenital malformations among blacks, Hispanics, American Indians, and Asians in the United States has not been previously documented. Results of several studies have suggested that the rates of some malformations vary by socioeconomic status, race, and ethnicity. This report provides the first estimates of the 15 leading major congenital malformations among four minority groups in the United States and identifies groups at higher risk for some congenital anomalies. Furthermore, it provides baseline rates that should prove useful in identifying trends and clusters of malformations among minority groups.

Although minor birth defects were not included in this report because they are not a significant cause of morbidity and mortality, BDMP data showed that rates of polydactyly, breast anomalies (mostly supernumerary nipples), branchial clefts, and anomalies of the abdominal wall (mostly umbilical hernias) are highest among blacks.

The data in this report must be interpreted with caution. Some of the overall differences in the distribution of malformations among different racial/ethnic groups may be explained as follows: 1) In some instances, physicians may tend to look for a particular malformation more in certain racial/ethnic groups than they would in others (detection bias). For example, some hospitals mainly serve minority groups believed to be at higher risk for some malformations. 2) Since BDMP data are not obtained from a random sample of U.S. hospitals, some of the participating hospitals may have a higher or lower than usual proportion of high-risk pregnancies and births. 3) Rates of congenital anomalies may be different in BDMP hospitals than in other hospitals because of their size or affiliation. 4) Socioeconomic factors, such as education, access to medical care, nutrition, maternal lifestyles, and cultural influences, cannot be ruled out as major contributors to the burden of some malformations among certain minority groups. 5) Many of these major congenital malformations may have been associated with genetic and environmental factors. 6) The heterogeneity within minority groups is not addressed in this report.

In conclusion, the importance of monitoring congenital malformations by race and ethnicity has been demonstrated, and notable differences in the overall distribution of these anomalies have been identified. Much work remains to be done in the fight against the number one cause of infant mortality, and public health professionals need to address the problem of why certain minority groups have a higher risk for some congenital malformations than other segments of the population.

Gilberto F. Chavez, M.D., M.P.H.; Jose F. Cordero, M.D., M.P.H.; Jose E. Becerra, M.D., M.P.H., Birth Defects and Genetic Diseases Branch, Division of Birth Defects and Developmental Disabilities, Center for Environmental Health and Injury Control.

In mid-March 1988, three family members in Orange County, California, became dizzy and nauseated within 1 hour of eating taquitos, a snack consisting of a corn tortilla wrapped around a meat filling. Two of the three subsequently had multiple grand mal (generalized convulsions with loss of consciousness) seizures. The taquitos, a commercial product sold frozen in sealed plastic bags of 48, had been purchased 5 days earlier.

After receiving the reports of illness, the County of Orange Health Care Agency (COHCA) requested that the product be removed from the shelves of the store where the implicated bag was purchased. Several remaining taquitos from the implicated bag were tested by the U.S. Department of Agriculture (USDA), Food Safety and Inspection Service, and found to contain endrin, a pesticide known to cause seizures. Samples of taquitos removed from the store and tested in USDA laboratories were negative for pesticides. The USDA reviewed the operations of the plant where the taquitos were produced, but no evidence of the pesticide was found. However, 90 cases of taquitos were destroyed by the plant owner as a precautionary measure. The USDA concluded that the poisonings were an isolated incident and closed the case April 20, 1988.

Subsequently, in September 1988, COHCA was informed of a 17-year-old boy who, in mid-March, had four seizures 30 minutes after eating taquitos purchased from the same store. After the seizures in March, he had been diagnosed as epileptic and begun on long-term anticonvulsants. At a hearing to determine the 17-year-old's continued eligibility for a driver's license, the hearing officer remarked that he had presided at a similar case (that of the father of the index family) the week before. (In California, seizures and loss of consciousness are reportable conditions for the purpose of determining eligibility for a driver's license.) This new information implicated a second bag of taquitos and indicated that other illnesses may have been misdiagnosed, resulting in serious medical and social consequences. Therefore, the investigation was reopened by the COHCA and the State of California.

A state-issued press release and a mailing by the store to over 40,000 customers generated 100 calls to the local health department. As a result of this publicity, two additional persons who had suffered seizures <12 hours after eating taquitos were identified. All five seizure patients had eaten taquitos purchased from the same discount store within a 5-day period in March. Families other than the index ( the first family which had the illness) family had no remaining taquitos.

California Department of Food and Agriculture laboratories confirmed the presence of endrin in leftover taquitos from the index family. Endrin was present in the tortillas but not in the meat filling. The store, the manufacturing plant, and the manufacturer's suppliers were thoroughly inspected, but no source of endrin was found.

Because of the limited nature of the outbreak and failure to find evidence of contamination in the plant inspections, the California Department of Health Services suspects deliberate tampering as the cause of the outbreak.

Editorial Note: Endrin is an extremely toxic chlorinated hydrocarbon pesticide in the family of pesticides that includes DDT, heptachlor, aldrin, and dieldrin. Symptoms of endrin poisoning include dizziness, nausea, tremors, leg weakness, disorientation, and tonic-clonic seizures. Endrin has been responsible for more than 1200 cases of illness and 45 deaths during outbreaks of foodborne poisonings in Wales, Qatar and Saudi Arabia, and Pakistan.

The Orange County episode is the first reported outbreak of endrin poisoning in humans in the United States. The registration of endrin for agricultural purposes in the United States was withdrawn in 1984, and it has not been manufactured in this country since that time. Nevertheless, supplies of endrin remain in this country, and other countries continue to use and manufacture the chemical.

V.Lead Poisoning Following Ingestion of Homemade Beverage Stored in a Ceramic Jug - New York

In the summer of 1987, seven persons living in Westchester County, New York, developed lead poisoning after ingesting a homemade beverage stored in a ceramic bean jug. The six adults and one child were relatives and lived at or frequently visited the home where the jug was kept.

The 140-ounce brown ceramic jug had been obtained in Mexico and is of a type commonly used to cook beans. The first person to experience illness used the jug to store a beverage he prepared frequently from sugar, water, and mara, a grain imported from Columbia. After the beverage fermented, family members consumed it several times daily throughout the summer.

In October 1987, the first patient -- a 67-year-old man -- consulted a physician because of severe abdominal pain, fatigue, and weight loss. The physician initially suspected gastric carcinoma. However, because severe anemia (hemoglobin 8 gm) and red blood cells with basophilic stippling were detected, a blood- lead level was obtained. Both the blood-lead level (70 ug/dL) and the erythrocyte protoporphyrin (EP) (382 ug/dL) were markedly elevated ( elevated EP is a sign of lead poisoning). He received chelation treatment for lead during a 2-week hospitalization.

After the initial case was diagnosed, a public health sanitarian visited the home to search for the source of lead. Interviews and a search of the premises identified the bean jug, which was severely corroded on the inside. Analysis of the jug by the New York State Department of Health (NYSDH) detected a lead content of 730 ppm, 100 times the normal value for a hollow vessel of this size.

Other household members were tested for lead. Six persons, aged 8-90 years, had elevated blood-lead levels (range: 35-70 ug/dL). An 8-year-old child had a lead level of 35 ug/dL and an EP of 152 ug/dL (CDC risk classification III [high risk]).* One of the five adults was also hospitalized.

Investigation by NYSDH revealed other earthenware with high lead contents in shops and bodegas in this town. The Westchester County Department of Health distributed bilingual fliers in ethnic communities in the county warning of the possible hazards from the use of ceramic ware.

No additional cases have been identified. All patients have been followed by their personal physician, and their blood values have returned to normal.

Editorial Note: Because of industrialization, lead is ubiquitous in the human environment. Common sources of lead exposure include lead-based paints (present on the interior surfaces of an estimated 30-40 million U.S. homes), airborne lead from combusted lead additives in gasolines or from factories using lead, occupations such as the production or repair of lead-acid storage batteries or automobile radiators, and a variety of ethnic remedies, particularly those used by Asian and South American groups. Although lead-glazed pottery is not a widespread source of lead, it can release large amounts of lead into food and drink. Lead-glazed pottery has been responsible for outbreaks of serious poisoning; in several episodes similar to this one, imported pottery has been implicated. Homemade or craft pottery and porcelain-glazed vessels can release large quantities of lead, particularly if the glaze is chipped, cracked, or improperly applied. If the vessels are repeatedly washed, the glaze may deteriorate, and pottery previously tested as safe can become unsafe. Acidic foods, beverages, or even water can leach lead from the containers.

Excessive absorption of lead is one of the most prevalent and preventable childhood environmental health problems in the United States. Once thought to be a problem confined to poor urban children, lead poisoning is now known to involve children in all socioeconomic strata. Although the toxic properties of lead affect all age groups, attention is generally focused on the serious consequences of elevated lead exposure on the developing central nervous system of children <6 years of age. The level in children at which further diagnostic follow-up is recommended is 25 ug/dL of lead in whole blood; however, recent studies have shown that blood-lead levels as low as 10 ug/dL may adversely affect childhood neurobehavioral function and development.

* CDC defines an elevated blood-lead level in children as a confirmed concentration of lead in whole blood of >25 ug/dL; lead toxicity is defined by an elevated blood level with an EP in whole blood of >35 ug/dL.

News Release from the US Department of Commerce National Oceanic and Atmospheric Administration

Hundreds of bottlenose dolphins that died off the east coast of the United States during the summer of 1987 and into early 1988 were poisoned by eating fish tainted by a naturally occurring toxin from "red tide" algae, according to the National Oceanic and Atmospheric Administration (NOAA).

The red tide alga, known as Ptychodiscus brevis, produces the powerful poison, brevetoxin, which killed some of the dolphins directly, NOAA said, and weakened others making them more susceptible to a host of bacterial and viral infections.

NOAA reported that this is the first known instance of the toxin's being transmitted to a mammal through tainted fish. The toxin itself was confined to the liver and other viscera of the fish. It is not present in the flesh and poses no threat to humans eating fish fillets, NOAA said.

The toxin was carried up the coast by fish--possibly menhaden or Spanish mackerel that had eaten menhaden--that had consumed the algae.

Red tides are normally confined to the Gulf of Mexico, although occasionally such algal blooms can be carried around Florida and swept north along the Atlantic coast by the Gulf Stream.

Dead dolphins first began washing ashore in southern New Jersey in late June 1987. In early August, NOAA and the Marine Mammal Commission assembled an investigative team in Virginia Beach, VA, to examine stranded dolphins, collect tissue samples and begin an analysis that would eventually involve almost 350 dolphins in thousands of separate tests. The team was headed by Dr. Joseph Geraci, a veterinarian working at the University of Guelph in Ontario, and at one point involved more than 100 volunteer scientists and others at dozens of federal, university and private agencies and laboratories. The brevetoxin analyses were carried out in the laboratories of Dr. Dan Baden at the University of Miami.

By March of 1988, when the event ended, about 740 dolphins had washed ashore from New Jersey to Florida. NOAA estimates a substantially larger number died and were lost at sea.