2.2.2 Oral Exposure -3 - GAZA兵器と人間・資料庫 @ wiki

TOXICOLOGICAL PROFILE FOR WHITE PHOSPHORUS -index
2 HEALTH EFFECTS
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

2.2.2 Oral Exposure -3

• 2.2.2 Oral Exposure
  • (2.2.2.0 preface)
  • 2.2.2.1 Death
• 2.2.2 Oral Exposure -2
  • 2.2.2.2 Systemic Effects

2.2.2.3 Immunological and Lymphoreticular Effects

There is limited information on the immunotoxicity of white phosphorus; however, there is some information that suggests that the immune system may be a target. Thymic hemorrhages were observed in two young children accidentally ingesting white phosphorus-containing fireworks (Dwyer and Helwig 1925; Humphreys and Halpert 1931). In one of these children, hyperplasia of lymphoid tissue in the intestinal wall and abdominal lymph nodes and hyperplastic lymphoid corpuscles in the spleen were observed (Humphreys and Halpert 193 1). Decreases in leukocyte levels were reported in a number of case reports involving acute ingestion of rat poison or fireworks containing white phosphorus (Diaz-Rivera et al. 1950; Ehrentheil 1957; Fletcher and Galambos 1963; McCarron et al. 1981; Newburger et al. 1948; Pietras et al. 1968). A decrease (Pietras et al. 1968) or an increase in the percentage of polymorphonuclear leukocytes (neutrophils) (McCarron et al. 1981) were also observed in individuals ingesting white phosphorus. Because the individuals vomited shortly after ingesting the white phosphorus and/or received gastric lavage, doses could not be estimated. In workers exposed to an unknown level of white phosphorus via inhalation, oral, and dermal routes, a decrease in leukocyte levels was observed (Ward 1928).

No studies were located regarding immunological or lymphoreticular effects in animals after oral exposure to white phosphorus.

2.2.2.4 Neurological Effects

A number of case reports of individuals accidentally or intentionally ingesting a single dose of white phosphorus have reported neurological effects. Nonspecific neurological effects including lethargy (Dathe and Nathan 1946; Fletcher and Galambos 1963; McCarron et al. 1981; Rao and Brown 1974; Rubitsky and Myerson 1949; Simon and Pickering 1976; Talley et al. 1972), sleepiness (Dwyer and Helwig 1925; Ehrentheil 1957; McCarron et al. 1981; McIntosh 1927), irritability (McCarron et al. 1981), restlessness (Diaz-Rivera et al. 1950; Ehrentheil 1957; Harm and Veale 1910), and hypoactivity (Humphreys and Halpert 1931) have been observed. Other symptoms of neurotoxicity that have been observed include coma or semi-coma (Caley and Kellock 1955; Ehrentheil 1957; Hann and Veale 1910; McCarron et al. 1981; McIntosh 1927; Wechsler and Wechsler 1951), toxic delirium and psychosis (Diaz-Rivera et al. 1950), hemiplegia (Humphreys and Halpert 1931; McCarron et al. 1981), abnormal reflexes (Wechsler and Wechsler 1951), hyperesthesia (Humphreys and Halpert 1931), coarse muscle fasciculations (Caley and Kellock 1955), unresponsiveness to painful stimuli (Simon and Pickering 1976), and marked asterixis (flapping tremor) (Greenberger et al. 1964). In addition to these overt signs of neurotoxicity, histological damage in the brain was observed in four individuals ingesting a single dose of white phosphorus. Based on this limited information, the types of cellular damage can be grouped into four categories: (1) cellular changes resulting from ischemic damage found in the Purkinje cells and cerebral cortical cells of the second and third layer of the cortex (Wertham 1932); (2) direct white phosphorus-induced cellular damage to the dentate nucleus and inferior olives (Wertham 1932); (3) fatty infiltration in the ganglion cells of the cortex, neuroglial cells, Golgi cells of the cerebellum, and the cells in the pia-arachnoid space (Humphreys and Halpert 1931; Wertham 1932); and (4) cerebral edema (Rao and Brown 1974). It is not known if the cerebral edema observed in this one individual was secondary to the other types of damage. A child treated with 0.083 mg/kg/day white phosphorus for an intermediate duration became lethargic 3 months after beginning treatment and remained lethargic until treatment was discontinued .70 days later. Following cessation of treatment, the child recovered very rapidly (Sontag 1938).

Overt signs of neurotoxicity were observed in a cat ingesting a single lethal dose (Fry and Cucuel 1969) and in pregnant rats exposed to a lethal dose (0.075 mg/kg/day) of white phosphorus for an intermediate duration (effects only observed during late gestation of parturition) (Bio/dynamics 1991). Tonoclonic convulsions, increased salivation and weakness were observed in the cat (Frye and Cucuel1969), and tremors were observed in pregnant rats (Bio/dynamics 1991). In another developmental toxicity study (IRDC 1985), no signs of neurotoxicity were observed in pregnant rats.

All LOAEL values from each reliable study for neurological effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Because vomiting occurred or the individuals received gastric lavage shortly after ingestion, reliable dose estimations could only be made for one individual acutely exposed to 2 mg/kg/day white phosphorus (Hann and Veale 1910).

2.2.2.5 Reproductive Effects

Extensive uterine hemorrhaging was observed in a 2-month pregnant woman following the intentional ingestion of 2 mg/kg white phosphorus in rat poison (Hann and Veale 1910). Autopsy results showed that the uterus was enlarged containing a hemorrhagic mole, which was consistent with a 2-month pregnancy. No effects on reproductive performance or histological alterations in the ovaries, uterus, testis, or epididymis were observed in rats administered 0.075 mg/kg/day or less in a one-generation reproduction study (Bio/dynamics 1991; IRDC 1985).

The highest NOAEL value and all LOAEL values from each reliable study for effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2.

2.2.2.6 Developmental Effects

A healthy infant was administered phosphorized cod liver oil (reported to contain 1.1 mg “pure” phosphorus per fluid ounce) from ages l-7 months (Sontag 1938). The phosphorized cod liver oil was apparently administered for the prevention of rickets. The time-weighted average dose for the 6-month exposure was 0.083 mg/kg/day. During the first 3 months of treatment, the child appeared clinically normal and grew at a normal rate. From the ages of .4 to 6 months, the child became clinically ill, gained essentially no weight, and the rate of growth in height decreased from .0.1 to 0.04 cm/day. Following replacement of the treatment with normal, nonphosphorized cod liver oil, the child appeared to recover quickly, and began to grow at a normal rate. Radiograms taken at 6 months of age showed bands of increased density at the end of all the long bones with increased thickness and density also observed in the zones of calcification. Radiograms taken between 9 months and 5 years of age showed bands of increased density in the diaphyses of the long bones, and in the pelvic, metacarpal, and metatarsal bones. This study describes formation of “phosphorus” bands of increased density in the ends of long bones and possible decreased growth in a child exposed to 0.083 mg/kg/day phosphorus for 6 months (Sontag 1938). It should be noted that radiologic densities are common at the growing points of long bones in children. However, lead poisoning, administration of nickel, certain chronic diseases like anemia, and hypervitaminosis D may also produce bands in the ends of bones, but these are much thicker and heavier (Sontag 1938).

A child with Perthes’ disease was administered 0.056 mgkg/day of phosphorus for two periods of intermediate duration, separated by a period with no exposure (Phemister 1918). “Phosphorus” bands of increased density developed in the ends in the tibia, fibula, and femur during the two exposure periods, without any improvement in the child’s condition. A male child with dyschondroplasia was administered

0.026 and 0.046 mg/kg/day white phosphorus for 3 and 8 months, respectively. “Phosphorus” bands of increased density developed in the tibia, fibula, and femur. The density and thickness of the bands were greater at the high-dose level and longer-treatment period. A male child with osteogenesis imperfecta was administered 0.078, 0.063, and 0.059 mg/kg/day phosphorus for 26,3, and 18 months, respectively, separated by a period of time with no white phosphorus exposure. Treatment with white phosphorus produced marked changes, including bands of increased density at the ends of bones and increased transverse diameters of the shafts of bones in the legs and arms (Phemister 1918). Four children with moderate to severe cases of rickets were treated orally with 0.110-0.158 mg/kg/day white phosphorus for durations ranging from 64 to 149 days (Compere 1930a). “Phosphorus” bands of increased thickness and density were observed in the long bones of 1 of 2 of the children examined.

An arachitic child was treated with 0.119 mg/kg/day white phosphorus for 82 days (Compere 1930b). Following treatment, the child had a “heavy phosphorus line” and increased density of cortices. Treatment with white phosphorus did not generally improve the condition of the bones in children with rickets. Because these children were sickly, the relevance of the observed effects to potential effects of white phosphorus in normal, healthy children could not be ascertained.

Young, growing rabbits exposed to 0.3 mg/kg/day white phosphorus given as a pill for an acute duration had transverse bands of increased density in metaphyseal regions of the tibia and fibula, compared to a control group (Adams 1938a). However, the percentage of calcium and phosphorus, and the calcium/phosphorus ratio in the metaphyseal and cortical regions of the right tibia was similar between treated and control animals. Young, growing rabbits exposed to 0.3 mg/kg/day white phosphorus given as a pill for an intermediate duration had average growth of the tibia of 0.27 mm/day, compared to 0.36 mm/day in the control group; however, no statistical analysis of the results was reported (Adams and Samat 1940). One rabbit had histological abnormalities in the tibia including decreased size of epiphyseal cartilage plate, as well as increased density in the metaphyseal zone with trabeculae that were greater in number and extended further into the diaphysis to a greater extent, compared to a control rabbit. The trabeculae were associated with a greater amount of calcified cartilage matrix. These effects probably resulted from a decrease in the normal rate of bone resorption during bone growth, resulting in decreased rate of growth of the tibia. Weanling rats exposed to 1.25 mg/kg/day white phosphorus in the feed for an intermediate duration had widening of the metaphyseal trabeculae, broadened metaphysis, and a slightly convex lateral contour of the proximal tibia, compared to a control group (Whalen et al. 1973). Osteocytes were small and elongated compared to those in the control group, and osteocytic osteolysis and chondrolysis were decreased or missing. In the treated rats, metaphyseal trabeculae extended deeper into the diaphysis than in the controls. These effects probably resulted from decreased bone resorption during bone growth, resulting in widening trabeculae and a denser metaphysis. Very similar results were observed in studies on growing rats (Adams and Sarnat 1940) and rabbits, but not in an adult rabbit (Adams 1938b). In rats, the doses varied from 0.002% to 0.05% yellow phosphorus (Adams and Sarnat 1940) and in rabbits, from 0.6 to 6 mg (Adams 1938b; Adams and Samat 1940).

A decrease in the number of viable pups and an increase in the number of stillborn pups was observed in the F1a and F1b offspring of rats exposed to 0.075 mg/kg/day; however, the incidence was not significantly (p<0.05) different from controls (IRDC 1985). These effects were not seen in a similarly designed reproduction study in which rats were administered 0.075 mg/kg/day (Bio/dynamics 1991). Neither of these studies found any significant differences in the occurrence of malformations or anomalies.

These NOAEL and LOAEL values from each reliable study for developmental effects in rats are recorded in Table 2-2 and plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans or animals after oral exposure to white phosphorus.

Genotoxicity studies are discussed in Section 2.5.

2.2.2.8 Cancer

No studies were located regarding cancer in humans or after oral exposure to white phosphorus. In the only chronic duration oral study in animals, no treatment-related histopathological lesions were observed in the lungs or other organs (not otherwise specified) in rats given .1.6 mg/kg/day white phosphorus in the diet for up to 479 days (Fleming et al. 1942). Only six rats per dose group were used.

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2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE