recommends that worker exposure to arsenic and its inorganic compounds, with the exception of arsine and lead arsenate, be controlled by requiring compliance with the following sections. The standard is designed to protect the health and safety of workers for a 40-hour week over a working lifetime. Compliance with all sections of the standard should prevent adverse effects of exposure to inorganic arsenic in the workplace air and by skin exposure. The standard is measurable by techniques that are valid, reproducible, and available. Sufficient technology exists to permit compliance with the recommended standard, The standard will be subject to review and will be revised as necessary. "Arsenic" is defined as elemental arsenic and all of its inorganic compounds except arsine and lead arsenate. "Exposure to arsenic" is defined as exposure above 0.01 mg As/cu m. Section 1 -Environmental (Workplace air) (a) Concentration: Occupational exposure shall be controlled so that no worker is exposed to a concentration of arsenic greater than 0.05 mg As/cu m of air determined as a time-weighted average (TWA) exposure for up to a 10-hour work day, 40-hour work week.#
Medical surveillance shall be made available as specified below for all workers occupationally exposed to arsenic, (a)
Preplacement and annual medical examinations shall include:
(1) Comprehensive or interim work history.
(2) Comprehensive or interim medical history,
14" x 17" posterior-anterior chest X-ray,
Careful examination of the skin for the presence of hyperpigmentation, keratoses, or other chronic skin lesions. Skin examinations shall be repeated bimonthly. Care shall be taken to observe and record the location, condition, appearance, size, and any changes in all such lesions. The following warning sign shall be affixed in a readily visible location at or near entrances to areas in which there is occupational exposure to arsenic. This sign shall be printed both in English and in the predominant primary language of non-English-speaking workers, if any.

# ARSENIC DANGER!
High concentrations of dust or spray mist may be hazardous to health.
Provide adequate ventilation.
Section 4 -Personal Protective Equipment and Work Clothing Subsection (a) shall apply whenever a variance from the standard recommended in Section 1 is granted under provisions of the Occupational Safety and Health Act, or in the interim period during the application for a variance. Until the arsenic exposure limit prescribed in Section 1 is met, an employer must establish and enforce, as provided in subsection (a)
-f this Section, a respiratory protection program to effect the required protection of every worker exposed.
(a) Respiratory Protection: Engineering controls shall be used to maintain arsenic concentrations at or below the prescribed limit.
Appropriate respirators shall be provided and used when a variance has been granted to allow respirators as a means of control of exposure in routine operations and while the application for variance is pending.
Administrative controls can also be used to reduce exposure. Respirators shall also be provided and used for nonroutine operations (occasional brief concentrations above the time-weighted average or for emergencies). For these instances a variance is not required, but the requirements set forth below continue to apply. Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: (2) Self-contained breathing apparatus with positive pressure in facepiece (1) For the purpose of determining the type of respirator to be used, the employer shall measure the atmospheric concentration of arsenic in the workplace when the initial application for variance is made and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the arsenic concentration; this requirement shall not apply when only atmosphere-supplying positive pressure respirators are used. The employer shall ensure that no worker is being exposed to arsenic in excess of the standard because of improper respirator selection, fit, use, or maintenance.
(2) Filters used shall be of the appropriate class, deter mined on the basis of exposure to arsenic dust or fume. If exposure is to gases and vapors in addition to arsenic dust or fume, appropriate respira tors shall be selected and used for protection against these agents, also.
The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided.
(5) Respiratory protective devices described in Table 1-1 shall be those approved under the provisions of 30 CFR 11, published in the Federal Register March 25, 1972.
Respirators specified for use in higher concentrations of arsenic may be used in atmospheres of lower concentrations.
The employer shall ensure that respirators are adequately cleaned, and that employees are instructed on the use of respirators assigned to them and on testing for leakage, (b) Protective Clothing:
(1) Where needed to prevent contact dermatitis from arsenic compounds, protective clothing shall be provided by the employer. This may include underwear, gloves, coveralls, dust-proof goggles, and a hood over the head and neck. When liquids are being processed in a manner that may result in splashes, impervious gloves, aprons, and splash goggles shall be used.
(2) Protective clothing shall be changed at least daily at the end of the shift,
Work clothing shall not be taken home by employees.
The employer shall provide for maintenance and laundering of protective clothing,
The employer shall ensure that precautions necessary to protect laundry personnel are observed when soiled protective clothing is laundered,

# Section 5 -Informing Employees of Hazards from Inorganic Arsenic
At the beginning of employment in an arsenic area, employees exposed to arsenic compounds shall be informed of all hazards, relevant symptoms of overexposure, appropriate emergency procedures, and proper conditions and precautions for safe use or exposure. Instruction shall include, as a minimum, all information in Appendix IV which is applicable to the specific arsenic containing product or material to which there is exposure. The
Information shall be posted in the work area and kept on file and readily accessible to the worker at all places of employment where arsenic is involved in unit processes and operations.
A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, proper maintenance procedures and cleanup methods, and that they know how to correctly use respiratory protective equipment and protective clothing. or wet methods, Cleaning may be performed by washing down with a hose, provided that a fine spray of water has first been laid down. Sweeping or other methods which can stir the dust into the air shall not be used, (b) Waste material shall be disposed of in a manner which will prevent exposure of humans and animals as well as air and water pollution.
(c) Arsenic trichloride shall be handled only in enclosed systems sufficient to prevent skin contact and to prevent worker exposure in excess of the environmental standard.

# (d)
Where there is possibility of arsenic trichloride contact with the skin, emergency showers shall be provided in readily accessible locations. Eye-wash facilities shall also be conveniently located.
(e) Procedures for emergencies, including fire fighting, shall be established to meet foreseeable events. Necessary emergency equipment, including appropriate respiratory protective devices, shall be kept in readily accessible locations. Only self-contained breathing apparatus with positive pressure in the facepiece shall be used for fire fighting.
Appropriate respirators should also be available for use during evacuation.
(f) Exhaust ventilation and enclosure of processes shall be used wherever practicable to control workplace concentrations.
(g) Air from the exhaust ventilation system shall not be recircu lated into work areas, and necessary measures shall be taken to ensure that discharge outdoors will not produce a health hazard to humans or animals.
(h) Due to potential skin irritation associated with respirator use and arsenic dust exposure, workmen shall be permitted to leave the work area every two hours to wash their face and obtain a clean respirator.  Arsenic is between germanium and selenium in the Periodic Table and as a member of Group V its physicochemical properties resemble those of phosphorus.
 Its principal valences are three and five, and it is ubiquitous,  being found in small amounts in soils and waters throughout the world, as well as in foods, particularly seafood.  Arsenic is a constituent of a number of minerals. For industrial and commercial uses, it is obtained primarily from the ores of metals in which it is present as an impurity,  removed as arsenic trioxide (arsenic (III) oxide, As203) during the smelting operation. This oxide is used in the manufacture of most other arsenic compounds, and is produced in the US as a byproduct in the smelting of copper ores.  Physical and chemical properties of arsenic and some of its more important inorganic compounds are given in Table XI-1.  Consumption of arsenic trioxide in the United States is estimated to range between 25,000 and 35,000 tons annually. Of this amount, 6,000 to 14,000 tons are produced in the United States.  Various arsenic compounds are used as pesticides.  Arsenic compounds are also used in pigment production, the manufacture of glass, textile printing, tanning, taxidermy, in antifouling paints, and to control sludge formation in lubricating oils. Metallic arsenic is used as an alloying agent to harden lead shot, and in lead-based materials. It is also alloyed with copper to improve its toughness and corrosion resistance.  Some occupations which have or in the past have had potential exposures to arsenic are listed in In his opinion, the etiologic factor was ionizing radiation in the mines.
The significantly increased risk  of cancer both of the ethmoidal sinuses and of the lung experienced by workers refining nickel by the nickel carbonyl process in Swansea, South Wales, was attributed to arsenic present as an impurity in the sulfuric acid used prior to 1924.

# Goldblatt
 has suggested that finely divided nickel formed by decomposition of the gaseous carbonyl and deposited in the lung or on the mucosa of the sinuses was responsible. Hueper  has demonstrated the carcinogenicity of powdered metallic nickel when inhaled for prolonged periods by guinea pigs and rats. The splashed region of the skin was drenched thoroughly with water and all the clothing removed very soon after the accident. The man was transferred to a hospital within 15 minutes, where he was found to be suffering from burns on both legs, conjunctivitis, and throat irritation. Despite the fact that he had been wearing a respirator, the man stated he had inhaled an irritating gas (a companion, also wearing a respirator, was unaffected).
The throat irritation became worse and laryngitis developed, followed by bronchopneumonia resulting in death 5 days after the accident. Autopsy revealed redness and congestion of larynx, trachea, and bronchial mucosae, red hepatization of the lower lobes of both lungs, and marked fatty degeneration of the liver. The liver was found to contain 3.0 ppm of arsenic trioxide, the hair 3.0 ppm, and the urine present in the bladder 3.5 ppm. Buchanan reported  that, in the opinion of the analyst making these estimations, the higher liver content five days after the accident indicated absorption over a period of time, probably through the skin, while the presence of arsenic in the hair suggested previous absorption.
Another fatality was reported by Delepine  after arsenic trichloride was spilled on one leg of a worker. After death, arsenic was found in high concentrations in all tissues examined (lung, liver, kidney, pancreas, stomach, heart, and blood), and it appeared that the trichloride had been inhaled as well as absorbed through the skin. The heart, liver, kidney, pancreas, and stomach were in a state of acute granulo-fatty degeneration. The direct cause of death was kidney failure, but the damage to the lungs, liver, pancreas, and heart also would have been fatal more or less rapidly.

# Effects on Humans
According to Frost  in his review of arsenic in biology, inorganic arsenicals are more toxic than the organic, and trivalent is more toxic than pentavalent arsenic, but he also pointed out that for any such generalization exceptions can be found. Arsenic is widely distributed throughout body tissues, but can be found in the hair and nails months after it has disappeared from the urine and feces.  Pentavalent arsenic is excreted faster than trivalent arsenic,  and some authorities  state that trivalent arsenic accumulates in the mammalian body, but
Frost  reported rapid excretion of all arsenicals. Schroeder and Balassa  and Frost  stated that arsenicals are oxidized in vivo from trivalent to pentavalent, and not reduced from pentavalent to trivalent.
On the other hand, as an explanation for the toxicity of some pentavalent arsenicals, Buchanan  suggested that pentavalent arsenic is slowly reduced to trivalent.
The presence of arsenic was illustrated by Schroeder and Balassa  in a variety of foods purchased in food stores. persons with no known arsenic exposure. The average urinary excretion was 0.08 mg As/liter, with 79% of the samples below 0,1 mg As/liter. The three highest levels reported were 2,0, 1.1, and 0,42 mg As/liter, and were attributed to probable consumption of seafood. The two highest average urinary excretions by individuals were 0.22 and 0.12 mg As/liter, These authors considered  seafood to be the main source of dietary arsenic. Shellfish in particular elevated the arsenic of test subjects.
In one test, three subjects with pretest levels of 0.01, 0.05, and 0.03 mg As/liter were given lobster tail for lunch. Four hours after eating, urinary levels were 1.68, 1.40, and 0,78 mg As/liter, respectively, but after 48 hours, values were approaching the pretest levels.
The excretion by humans of inhaled arsenic was studied experimentally by Holland et al,  Eight terminal lung cancer patients inhaled smoke from a cigarette contaminated with As-74, and 3 others inhaled an As~74 aerosol from an intermittent positive pressure machine. Uptake and distri bution was determined by examining the chest with a radiation counter. The radioactive arsenic disappeared from the respiratory tract very rapidly during the first few days, falling by the forth day to 20%-30% of the original uptake. Thereafter, the rate of disappearance tapered off slowly.
Approximately 28% of the absorbed As-74 was excreted in the urine the first day. By the end of 10 days, urinary and fecal excretion of the absorbed As-74 was approaching zero, with 45% having been excreted in the urine and 2.5% in the feces. The remainder was assumed to have been deposited in the body, exhaled, or eliminated over a long time period. Deposition in hair, skin, and nails or in organs such as the liver was not reported.
The typical symptoms of severe chronic arsenicalism were illustrated in a case history reported by McCutchen and Utterback.
 The first symptoms were an attack of nausea, vomiting, diarrhea, hot flashes, and progressive anxiety. These symptoms gradually cleared over a period of 10 days.
Similar episodes continued intermittently. Within the next 2 years there was a gradual darkening of the skin, and a thickening and scaling of the skin on the soles of the feet, An almost constant pain and feeling of "pins and needles" appeared first in the feet and later in the hands.
Muscular weakness became more apparent and the extremities became numb in a glove and stocking distribution. Three years after the first symptoms, the skin of the trunk had darkened markedly, there had been a gradual loss of vision, and increased pain. Attacks of the initial symptoms continued to occur 3 to 4 times annually for 10 years, until the patient was referred to specialists for management of severe heart failure and muscular dystrophy.
At that time, ascites was evident and severe ankle edema had developed.
The patient was constipated except during the episodes of nausea and vomiting, when he had diarrhea. He was emaciated and had a diffuse tan pigmentation over the trunk. The palmar and plantar surfaces were hyperkeratotic and Mees lines were present on the nails. There was an erythematous macular-papular rash below the knees, with indolent, shallow ulcers up to 1 cm in diameter. All sensory functions were diminished in a diffuse peripheral nerve distribution with a definite increase in perception from distal to proximal. The patient could not walk. As/100 g of hair. The nails contained an average of 9.12 mg As/100 g of nails, with a range of 0.0 to 42.0 mg As/100 g of nails.
In all 6 cases anemia and leukopenia were present, with thrombo cytopenia in 3 cases.  White counts of less than 1000 were seen in 3 cases, with the major change an absolute neutropenia. All patients had relative eosinophilia, but the absolute eosenophil count was elevated in only one case. Basophilic stippling was a prominent finding. The bone marrow of 4 patients was examined, and in 3 of these increased, disturbed erythropoiesis was observed. Depressed or disturbed myelopoiesis was seen in all four. Hematologic abnormalities disappeared within 2 to 3 weeks after cessation of arsenic ingestion.

# Butzengeiger
 examined 180 vinedressers and cellarmen with symptoms of chronic arsenic intoxication and reported that in 41 (22.8%)
there was evidence of vascular disorders in the extremities. Arsenical insecticides were used in the vineyards and workers reportedly were exposed not only when spraying but also by inhaling arsenic-contaminated dusts and plant debris when working in the vineyards. The homemade wine consumed by most of the workers was believed to be contaminated with arsenic.
Fifteen cases were described in detail.
 All had varying degrees of hyperpigmentation and all but 2 had palmar and plantar keratoses. Cold hands or feet or both were common to all and apparently preceded the development of gangrene on the toes or fingers in 6 of the 15 cases. Liver damage was reported in 9 of the 15 cases, but most of the workers consumed up to 2 liters of wine daily. Urinary arsenic levels were given in terms of arsenic trioxide either per liter or per 100 grams of urine. Converting all to milligrams of arsenic per liter of urine (assuming a specific gravity of 1.024), values ranged from 0.076 to 0.934 mg As/liter, with an average of 0.324 mg As/liter. Arsenic in hair ranged from 0.012 to 0.1 mg As203/100 g of hair (0.009 to 0.076 mg As/100 g) with an average of 0.051 mg As203/100 g (0.039 mg As/100 g).
In  The ECG changes could not be related to disturbances in serum electrolytes and were considered due to a toxic effect on the myocardium.
In the acute case, approximately 24 hours after arsenic was ingested, the serum arsenic level was 0.0173 mg As/100 ml and the urinary level was 1.40 mg As/liter. Seventeen days after the arsenic was ingested, none could be detected in the serum but the urinary level was 0.5 mg As/liter. In the chronic cases, arsenic levels were: 0.060 and 0.059 mg As/100 g of hair;
1.92 and 2.61 mg As/100 g of nails; and, in the urine, 0.30 and 0.124 mg As/24 hours, respectively.
Franklin et al  observed 3 cases of portal cirrhosis which they attributed to prolonged use of Fowler's solution (potassium arsenite). One patient had taken Fowler's solution for 2 years for leukemia. The other patients had taken the medication for 2 and 6 years, respectively, for dermatologic conditions. All had generalized mottling and bronzing of the skin, palmar and plantar hyperkeratoses, ascites, and marked ankle edema.
Portal cirrhosis was diagnosed in all 3 cases and confirmed in 1 case by biopsy. There was no history of alcoholism in these cases. Urinary arsenic was elevated in only 1 case at 1.68 mg As/liter. The urinary levels in the remaining 2 cases were said to be normal, these investigators considering 0.0 to 0.06 mg As/liter as normal. However, it also occurred on the scrotum, the inner surfaces of the thighs, the upper chest and back, the lower legs, and around the ankles. Once established, dermatitis continued as long a3 arsenic exposure continued.
To permit the condition to clear up, sick leave was granted. The average length of sick leave required was 13.6 days for initial occurrences and 10.2 days for recurrences. Hyperpigmentation and keratoses were not reported.
Patch tests demonstrated that the dermatitis was due to arsenic, not to impurities present in the crude arsenic trioxide.
 Tests with arsenic trioxide and pentoxide, sodium arsenite, and sodium, calcium, and lead arsenate demonstrated that all produced dermatitis. Many workers had been sensitized to both trivalent and pentavalent arsenic. However, Holmqvist also recommended that workers with mild dermatitis, especially new employees, continue work since this often resulted in hyposensitivity.
The incidence of dermatitis was highest in those areas in which arsenic- exposure was highest, but occurred in all areas, possibly in sensitized individuals where arsenic exposures were low. Dermatitis also was worse in the summer months, possibly because workers sweat more than in the winter.

# An outbreak of arsenical dermatoses was reported by Birmingham et al
 which involved cases in the community outside the plant. A reactiva ted gold mine began smelting ore which contained large amounts of sulfides of arsenic. It was estimated that 40 tons of arsenic and 100 tons of sulfur dioxide were burned off daily, but the dust-collecting system failed to operate at the expected 90% efficiency. Within a few months after oper ations began, children attending elementary school in the nearby mining camp community developed skin lesions, mostly on the exposed parts of the body, Thirty-two of the 40 elementary school students had one or more types of suspect arsenical dermatoses including eczematous contact dermati tis, folliculitis, furunculosis, pyodermas, and ulcerations. Conjunctiv itis and rhinitis were common. The eczematous dermatitis was pruritic, usually involving the face and flexures, and was highly suggestive of atopic dermatitis. The follicular and pustular lesions were mostly on the face and neck, although some were on the extremities. Ulcerations were seen on the palms, fingers, toes, and webs. The high school students who spent 10 to 12 hours a day away from the community did not have dermatitis.
Nine of eighteen mill workers on the day shift had similar skin lesions. both in hair and in urine, exposed workers had significantly higher levels than did the unexposed controls. The three exposed groups did not differ significantly with respect to arsenic in hair, but the urinary excretion of arsenic by chemical workers was significantly higher than the excretion by maintenance workers and packers.
The workers were given a full physical examination with particular attention to pigmentation and the number of warts,  They were given a chest X-ray, a vital capacity test, and an exercise tolerance test. One worker showed an enlarged mass at a hilum, but bronchoscopy did not reveal a neoplasm. Otherwise, no abnormal results of the X-ray, vital capacity tests, or exercise tolerance tests were mentioned. Pigmentation keratoses and wart formation were considered quite typical of arsenic exposure, and "changes were so evident that the person carrying out the physical examination could readily tell whether the man he was examining was a chemical worker without asking any questions," The degree of pigmentation was subjectively rated as from one to four plus and the number of warts was recorded. Nine of the 31 chemical workers examined had from 1 to 6 warts, and their pigmentation was rated as negative in 3 workers, 1 plus in 10, 2 plus in 9, 3 plus in 7, and 4 plus in 2. Of 20 maintenance workers and 12 packers: 1 had 4 warts and pigmentation was rated as negative in 20 workers, 1 plus in 9, and 2 plus in 3. Of the 56 controls, 2 had 1 wart each and pigmentation was rated as negative in 46 workers, 1 plus in 8, and 2 plus in 2 (both of these were former chemical workers). miles, and 0.02 ppm at a distance of 2.0 to 2.4 miles. Samples of vacuum cleaner dust were also collected, and arsenic was reported to decline from 1300 ppm at a distance of 0 to 0.4 miles to 70 ppm at a distance of 2.0 to 2.4 miles. This suggests that arsenic exposure was not confined to one section of the smelter, but extended also to the surrounding community.
Thus, the "nonexposed" smelter workers might also have had a degree of arsenic exposure.
Effects observed,  presumably among the "exposed" workers, were dermatitis, perforation of the nasal septum, conjunctivitis, turbinate inflammation, and pharyngitis. Blond and reddish skinned persons were reported to be more sensitive to the irritating action of arsenic. Some cases of dermatitis were attributed to hypersensitivity, The authors considered dermatitis to be dependent on the sensitivity of the individual and on the degree of skin contact with arsenical dusts. Dust-in-air measurements were considered of limited value in predicting skin reactions, as were levels of arsenic in urine. However, based on a study of 127 individuals, the authors reported that dermatitis was observed in 80% of those excreting 1,0-3.0 mg As/liter and in 100% of those excreting more than 3.0 mg As/liter. No excessive pigmentation or keratoses were seen, and all observed effects were considered preventable by faithful use of the protective clothing and respirators described,
In a later paper based on the same plant population, Pinto and
Bennett  analyzed the causes of death for a total of 229 active plant employees and pensioners. The pensioners were defined as being at least 65 years of age at the time of the study, and as having had at least 15 years service in the plant. The total population at risk is not known since the study excluded all workers who left the plant before retirement. Neverthe less, the authors stated that the mortality figures "truly represent the causes of death in this plant for the individuals who stay long enough to have significant contact with industrial dusts and fumes. There was a decrease in the proportion of deaths due to cancer of the digestive organs and peritoneum (18.6% vs 34.5%).
The deaths in the smelter group were also classified into deaths among ' 'exposed" and "nonexposed" workers, revealing that relatively more cancer deaths occurred among the "nonexposed" (19.4% of all deaths) than among those "exposed" to arsenic (15.8%).
Compared to the data for the state as a whole, the smelter workers were also shown  to have slightly increased mortality due to cardio vascular disease (65,5% of all deaths compared to 59.0% in the state as a whole), but the increase was not statistically significant. An excess was observed in the 45-64 age bracket for both "exposed" and "nonexposed" workers (36.8% and 25.7%, respectively, compared to 15.2% for this age group in the state as a whole), with a reduction in cardiovascular mortality in the 65-94 age bracket for both groups (31.6% and 36,6%, respectively, compared to 41.9% in the state.) Because the cardiovascular mortality was similar in both "exposed" and "nonexposed" groups, the authors concluded that arsenic exposure had no effect.
The "exposed" and "nonexposed" categories are suspect, however, since For comparison, the mortality statistics were used for the white male population of the states in which the various smelters were situated.
 The total mortality of smelter workers was significantly increased.
The specific causes of death which were significantly elevated were tuberculosis, respiratory cancer, diseases of the heart, and cirrhosis of the liver. Respiratory cancer mortality was significantly increased in all 5 cohorts. Mortality due to diseases of the heart was significantly increased in cohorts 2, 3, 4, and 5. Deaths due to cirrhosis of the liver were significantly elevated to cohorts 2 and 5, while tuberculosis mortality was significantly higher only in cohort 5.
When respiratory cancer deaths were grouped according to relative level of arsenic exposure, the observed mortality was significantly higher than expected in all 3 groups: approximately 6.7, 4.8, and 2.4 times expected in the heavy, medium, and light exposure groups, respectively.
 In addition to arsenic trioxide, the smelter workers were simultaneously exposed to sulfur dioxide in over 5,000 of the cases, to silica in an unstated number of cases, to lead fume in 35 cases, and to ferromanganese dust in 317 cases. Therefore, a similar classification was made for relative sulfur dioxide exposure. Respiratory cancer mortality was directly related, with observed deaths ranging from 6.0 to 2.6 times expected in heavy, medium, and light exposure groups. Most work areas having heavy arsenic exposure were also medium sulfur dioxide and all jobs with heavy sulfur dioxide exposure were medium arsenic areas. It was observed that xrorkers with heaviest exposure to arsenic and moderate or heaviest sulfur dioxide exposure were most likely to die of respiratory cancer. Smoking histories were not available for the workers in this study, but the authors discounted smoking as the major factor, concluding that "it is highly unlikely that smoking alone would account for the excessive respiratory cancer mortality observed." Furthermore, there was no reason to expect that the amount smoked would be related to either the degree of arsenic or sulfur dioxide exposure.

# Animal Toxicity
The acute oral toxicity of arsenic trioxide in mice and rats was tested by Harrisson et al  using both "crude" or commercial grade (97.7% As203 with 1,18% Sb203) and highly purified arsenic trioxide (99,999+% As203). Solutions were administered intraesophageally using an oral feeding tube. Test animals had been previously fasted for 24 hours.
The acute oral LD50 for young Webster Swiss mice was estimated as 39.9 mg As/kg for the purified trioxide and as 42.9 mg As/kg for the commercial grade. For Sprague Dawley albino rats the LD50 was 15.1 mg As/kg and 23.6 mg As/kg for the pure and crude preparations, respectively. Despite its lower LD50, the purified arsenic was found to be less severe as a gastrointestinal irritant than was the crude trioxide. Retching during life and marked gastrointestinal damage at autopsy were observed only in animals receiving the crude arsenic trioxide. This was attributed to the antimony in the crude preparation.
Sharpless and Metzger [51J conducted a series of feeding experiments to investigate the relationship between arsenic and iodine. Young rats were fed basal diets with arsenic trioxide or pentoxide and potassium iodide added in varying ratios. Two control groups received the basal diet plus potassium iodide at one of two concentrations. In the one group receiving arsenic trioxide and potassium iodide, no effects were observed relative to the controls. The authors considered it "probable that insufficient arsenic was absorbed to exert either a toxic or goiterogenic effect."
In rats receiving nontoxic amounts (0.005% of the diet) of arsenic pentoxide, "a slight, but not significant" goiterogenic effect was observed.
 When arsenic was 0.02% of the diet, growth was decreased by 50% and the authors calculated that the iodine requirement was more than doubled. Thyroid weights were significantly increased while the iodine concentration in the thyroid decreased, even when iodine was administered at 5 times the minimum requirement. The authors suggested  that in man, arsenic in nontoxic amounts has an insignificant effect, but that in areas where the iodine intake is relatively low, a goiterogenic effect could be expected if the arsenic intake were sufficient to be slightly toxic.
Similarly, Dubois et al  reported antagonistic effects between arsenic and selenium. Albino rats given sodium arsenite or arsenate either in drinking water or in the diet were protected against toxic effects of seliniferous wheat, sodium selenite, and selenium-cystine. Arsenic sulfides (AsS2 and AsS3) in the diet did not prevent selenium poisoning.
Arsenic in drinking water was effective if administration began within the first 20 days of selenium administration. After 30 days of selenium in the diet, arsenic provided no protection. Rozenshtein  conducted an experimental inhalation study using albino rats. He was concerned with the effects of atmospheric pollution by arsenic trioxide on the community at large, so three groups of female albino rats were exposed 24 hours a day for three months to a condensation aerosol of freshly sublimed arsenic trioxide at levels of 0.06, 0.0049, and 0.0013 mg As203/cu m (approximately 0.046, 0,004, and 0,001 mg As/cu m ) .
The animals were studied biochemically and neurophysiologically during each month of exposure and during the recovery period after the termination of exposure. Some animals were killed one month after exposure ended and tissues were examined histologically and histochemically. The author did not state how many animals were involved in the study.
Inhibition of blood cholinesterase activity was detected during the exposure and recovery periods only in the high exposure group. In this same group, an increase in blood pyruvic acid concentration was detected.
Free -SH groups in whole blood also were lower and remained low after a month's recovery period. A disturbance of the normal chronaxial ratio of antagonistic muscles was seen in the two highest exposure groups, and was still apparent one month after exposure in the highest exposure group. Some accumulation of arsenic, mostly in the lungs and liver, was shovm at the end of the exposure period in the two highest exposure groups. In the most heavily exposed animals these organs retained a high arsenic content one month after exposure.
Microscopic examination of the brains of animals in the highest exposure group showed pericellular edema and plasma-cell infiltration of vascular walls, plasmolysis, and karyolysis in addition to shrivelling of neurons in the middle pyramidal tract.
In the bronchi of these animals there was accumulation of leukocytic exudate, and in the liver there was fatty degeneration of hepatic cells. There were less marked changes in the tissues of the intermediate exposure group. Unexposed animals were used as controls for the above observations.
The animals exposed to only 0.0013 mg As203/cu m (0.001 mg As/cu m)
showed none of the foregoing ill effects.
On this basis the author proposed  0.001 mg As203/cu m as the "mean diurnal maximum permissible concentration of this compound in the atmosphere...." This was apparently intended to be a standard for the population-at-large implying 24-hour exposure.
Another animal inhalation study with arsenic trioxide which in some respects more closely approaches human occupational exposure was conducted by Bencko and Symon.
In this case hairless mice were used to eliminate the possibility of ingesting fur-retained dust during grooming.
The animals were exposed 6 hours daily, 5 days a week for up to 6 weeks to fly ash containing 1% arsenic trioxide. Particle size was less than 10 microns, and the mean air concentration of arsenic was 0.1794 mg/cu m.
Mice were killed serially after 1, 2, 4, and 6 weeks of exposure, and the liver, kidney, and skin analyzed separately for arsenic content. No micro scopic examination of tissues was performed and there was no statement as to whether the animals were pathologically affected in any way.
Arsenic levels in liver and kidney peaked at 2 weeks exposure.
 At 4 and 6 weeks arsenic content fell to much lower levels, only slightly higher than in nonexposed controls despite continuing exposure. This implies that, after an initial latent period, the excretory mechanisms for arsenic increase in capacity and maintain an increased level for at least 6 weeks in the mouse, preventing accumulation of arsenic in liver and kidney.
In the skin, the arsenic content continued to rise until the fourth week of exposure. By the sixth week, the arsenic level had declined by about onethird and remained a little higher than at the end of the first week of exposure.
It does not appear that any of the mice died from the effects of their exposure during the experiments.
These results confirmed an earlier paper by Bencko and Symon  in which they reported studies of arsenic in the skin and liver of hairless mice given arsenic in their drinking water. Arsenic trioxide was administered in a 32-day subchronic experiment and in a 256-day experiment.
In both experiments, the maximum arsenic content of the skin and liver was reached on the 16th day. Thereafter, arsenic values decreased in the skin and liver, being particularly manifest in the long-term experiments. The rats tolerated the arsenic solutions well and gained weight, but the mice died rather early.
With the exception of leukemia in one mouse receiving pure water, there were no cancers in mice,  The highest number of cancers in rats occurred among those on the alcoholic solution of arsenic, but they did not differ in type from those in the control groups. The rats receiving pure water had the highest incidence of reticulum cell sarcomas of the liver.
There was one skin cancer (a squamous cell carcinoma of the cheek) in this control group, identical in site and type to the 2 skin cancers observed in the principal experimental group, the group receiving arsenic in alcoholic solution.
Baroni et al  tested both arsenic trioxide and sodium arsenate for primary carcinogenic effect, for cancer initiating effect in combina tion with the promoter croton oil, and for cancer promoting effect fol lowing administration of the carcinogens 7, 12-dimethyl benz(a)anthracene and urethan, in mice, The arsenic trioxide was administered as a 0.01% solution in the drinking water, and the sodium arsenate was applied to the skin of the mice as a 1.58% solution in a 2.5% solution of detergent. The results were entirely negative for all three types of effect.
Osswald and Goerttler  observed a marked increase in the incidence of lymphocytic leukemias and malignant lymphomas in female Swiss mice and their offspring following subcutaneous injections of arsenic.
Injections of a 0.005% aqueous solution of the "sodium salt" (the valence of the arsenic was not specified) were given daily during gestation (a total of 20 injections) in a dose of 0.5 mg As/kg. The leukemia rate was increased both in the females (11 of 22 deaths due to leukemia) and in their offspring (13 of 59 deaths). The leukemia rate was further increased when arsenic was injected subcutaneously into the offspring themselves (41 miles.
-f
The arsenic content of vacuum cleaner dust also declined with distance from the smelter. This suggests that there may have been a degree of arsenic exposure in the "nonexposed" group since arsenic apparently escaped to the community outside the smelter.
The "exposed" workers' average excretion was 0,82 mg As/liter. Of those found to be excreting 1.0 to 3.0 mg As/liter, 80% had dermatitis. Everyone excreting over 3.0 mg As/liter had dermatitis.
Studying the same plant population, Pinto and Bennett  reported increased mortality due to respiratory cancer and cardiovascular disease, but the increase was not statistically significant. The incidence of deaths for these causes was similar among "exposed" and "nonexposed" workers, so the authors concluded that the deaths were not related to arsenic exposure. As already pointed out, however, the urinary arsenic levels reported by Pinto and McGill  suggest that there was a degree of arsenic exposure in the "nonexposed" group, A 1973 study of this plant population by Milham and Strong  demonstrated significantly increased lung cancer mortality. No environmental data were collected in this study, so the incidence of cancer cannot be related to exposure,
A study of a larger smelter population was reported by Lee and
Fraumeni.
 In this case, overall mortality was significantly higher than expected. Specific causes of death which were significantly higher than expected were diseases of the heart, tuberculosis, cirrhosis of the liver, and respiratory cancer. Of these, only respiratory cancer was significantly higher in all cohorts. Furthermore, respiratory cancer mortality was .directly related to length of employment, and to both the degree of arsenic exposure and the degree of sulfur dioxide exposure.
Because there was considerable overlap between these exposure groups, it was not possible to separate effects due to each, but it was found that workers with heavy arsenic exposure and moderate or heavy sulfur dioxide exposure were most likely to die of respiratory cancer. Assuming these data to be representative, they indicate that arsenic exposures in the "heavy" and "medium" exposure areas were very similar overall, although concentrations reached higher levels in the heavy exposure area. However, even in the "light" exposure areas, where in these samples the average air concentration was 0,206 mg As/cu m, respiratory cancer mortality was significantly increased over the expected incidence.
The animal study with the most direct bearing on an occupational exposure standard is that by Rozenshtein  in which rats were exposed 24 hours a day to an aerosol of arsenic trioxide at concentrations of 0,06, 0,0049, and 0,0013 mg As203/cu m (approximately 0,046, 0,004, and 0,001 mg As/cu m). One difficulty with this study is that, as grooming animals, the Engineering Controls Significant exposures are encountered both in the production of arsenic compounds and in their use, and good industrial hygiene practices must be followed to prevent adverse health effects. Where fumes may be present, as in the sintering and roasting of arsenic-bearing ores, complete enclosure and exhaust ventilation of the operation is essential.
Operations that agitate arsenic trioxide dust, eg grinding, screening, shoveling, sweeping, and transferring, require control since the dust is very fine and disperses easily.
 When the operation has not been sufficiently enclosed and ventilated, supplemental protective clothing and respiratory protection may be needed until adequate engineering controls are installed.
Arsenic trichloride can cause irritation or ulceration on contact or may be absorbed through the skin with fatal results.  Since its vapor pressure at 25 C is sufficient to produce an air concentration of 14,000 ppm (104,000 mg/cu m) ,  its handling requires complete enclosure.
Agricultural uses of arsenic compounds may produce potentially hazardous exposures for nearby personnel. Engineering control methods used will depend on the equipment and techniques used to apply the chemicals.
Protective clothing and respiratory protection may be needed as supplemental controls.

# Biologic Evaluation
Arsenic absorbed into the human body is excreted in the urine, feces, skin, hair, and nails, and possibly a trace from the lungs.  Even at low doses, a proportion of absorbed arsenic is deposited in the skin, hair, and nails where it is firmly bound to keratin.
 Storage in these metabolically "dead" tissues represents a slow route of elimination from the body.
Arsenic in hair has been used to monitor workers' exposure,  but the significance of arsenic in hair is obscured by the difficulty of distinguishing externally deposited arsenic from that systemically deposited in the hair. Camp and Gant  reported that "there is no way to differentiate 'interior' and 'exterior' arsenic." Similarly, Watrous
and McCaughey  reported that once arsenic was deposited on the hair, it resisted washing with ether and water, and they considered determinations of arsenic in hair to be completely unreliable. The level of arsenic in fingernail and toenail parings reflects past absorption and is therefore useful forensically, but is less useful if the goal is to monitor current absorption.
Most authors agree that the urine is a major route of arsenic excretion.  Arsenic can be detected in the urine of people with'no known exposure to arsenic, apparently derived from dietary and general environmental sources.  However, the urine of workers occupationally exposed to arsenic may show much higher levels than that of the unexposed, even in the absence of signs of systemic arsenic poisoning.  Webster  collected urine samples from 26 adults and 17 children and reported that the average arsenic content was 0.014 mg As/liter with an average specific gravity of 1.017, Corrected to a specific gravity of 1.024, Webster's average was 0,02 rag As/liter.
Schrenk and Schreibeis  collected 756 urine specimens from 29 persons with no known industrial exposure to or abnormal dietary uptake of arsenic.
The overall average urinary excretion was 0.08 mg As/liter, and 79% of the samples were less than 0.1 mg As/liter. After the authors found that seafood could affect urinary arsenic levels, they excluded values when it was known that the subject had eaten seafood. However, some values, which apparently had been influenced by seafood, were included beifore sea food was recognized as a factor. Since no record of diet had been kept, these unusually high values could not be excluded (the three highest samples were 2.0, 1.1, and 0.42 mg As/liter).
Seafood was considered  to be the main source of dietary arsenic.
Shellfish in particular elevated the arsenic of test subjects. In one test, three subjects with pretest levels of 0,01, 0.03, and 0,05 mg As/liter were given lobster tail for lunch. Four hours after eating, urinary levels were 1.68, 0.78, and 1.40 mg As/liter, respectively, Ten hours after eating, levels were 1.02, 1.32, and 1.19 mg As/liter. After 24 hours values were 0.39, 0.39, and 0.44 mg As/liter, and at 48 hours, values were approaching the pretest levels.
Rapid initial excretion of inhaled arsenic was reported by Holland et al,  with 28% of the absorbed As-74 being excreted in the urine within the first day after it was inhaled, and 45% within 10 days. An additional 2.5% had been excreted in the feces after 10 days} but the remaining 52,5% was not accounted for.  Some of the unexposed individuals tested had urinary levels as high as 2.0 mg As/liter,  but these high levels may have been due to unusual dietary intake  or to unrecognized arsenic exposure.
The urinary arsenic levels of exposed workers vary widely and levels to 2,000 urine samples annually since the Levine and Fahy report, and 1.024 is still the mean specific gravity used. However, care must be exercised when making specific gravity corrections to express the specific gravity of the urine in relation to that of water at the same temperature. If a urinometer calibrated against water at 4 C is used, then a correction for temperature should also be employed.  Citing urinary levels reported by Pinto and McGill  for exposed workers with no signs of poisoning, Schrenk and Schreibeis  concluded that, while no relationship could be shown between urinary arsenic levels and evidence of poisoning, "urinary arsenic levels in a group of exposed persons may serve to check the efficacy of control measures and indicate if excessive absorption of arsenic occurs." Referring to the inconsistency with which the workers wore their respirators, Pinto and Bennett  wrote: "It is for this reason we depend on the urinary arsenic level as showing the men are exposed to arsenic-containing dusts. The simple measurement of arsenic dust in the air is not a good measure of how much arsenic has been absorbed by an individual."
Monitoring urinary arsenic cannot replace monitoring atmospheric concentrations as the primary method of characterizing the workers' exposure, It seems reasonable that group averages may be useful as a check on the adequacy of the overall program of engineering controls and work practices designed to protect the workers' health.
V.

# DEVELOPMENT OF THE STANDARD

# Basis for Previous Standards
The American Standards Association (now the American National Standards Institute) in 1943 proposed 0.015 mg As/cu m as an American War
Standard for inorganic arsenic.
 However, the summary of standards compiled by Cook  shows that by 1945 the War Standard had been increased by a factor of 10 to 0.15 mg As/cu m, set on the basis of analogy with other metals such as cadmium and lead. The 0.15 mg As/cu m standard was also adopted by Connecticut, Massachusetts, New York, and Oregon, but In his 1959 textbook, Elkins   of a copper smelter reported that observed deaths due to cardiovascular disease exceeded the expected, but the difference was not statistically significant. Another study  of a smelter population found that, compared to statistics for the state in which the smelter was located, mortality due to heart disease was significantly increased. In terms of length of employment, cardiovascular mortality was significantly increased in 4 of 5 cohorts, and the excess mortality was approximately the same in each of these 4 cohorts.
In both smelter studies,  exposures were to many compounds other than arsenic. However, the fact remains that arsenic apparently caused at least temporary ECG changes  and may have caused increased cardiovascular mortality,  Cirrhosis of the liver has been reported as a result of prolonged use of Fowler's solution  and among German vineyard workers.  In the latter studies, ethyl alcohol may have been at least a contributor, since in one report   Because of the seriousness of the disease, prudence dictates that the standard should be set at least as low as 0,05 mg As/cu m. It is believed that exposure at this level should, at the minimum, significantly reduce the incidence of arsenic-induced cancer.
(d)
A minimum of three samples shall be taken for each operation (more samples if the concentrations are close to the standard) and averaged on a time-weighted basis.
(e) A minimum of three blank filters carried in closed cassettes to the sampling site shall be provided to the analytical laboratory to determine the background correction which must be applied to the analytical results,

# Calibration of Sampling Trains
Since the accuracy of an analysis can be no greater than the accuracy of the volume of air which is measured, the accurate calibration of a sampling pump is essential to the correct interpretation of the volume indicated. The frequency of calibration is dependent on the use, care, and handling to which the pump is subjected. In addition, pumps should be recalibrated if they have been subjected to misuse or if they have just been repaired or received from a manufacturer. If the pump receives hard usage, more frequent calibration may be necessary.
Ordinarily, pumps should be calibrated in the laboratory both before they are used in the field and after they have been used to collect a large number of field samples. The accuracy of calibration is dependent on the type of instrument used as a reference. The choice of calibration instrument will depend largely upon where the calibration is to be performed. For laboratory testing, a 1-liter burette or wet-test meter is recommended, although other standard calibrating instruments such as spirometer, Marriott*s bottle, or dry-gas meter can be used. The actual set-up will be the same for these instruments. Calculations: If a 25 ml aliquot of a 50 ml prepared sample is taken for analysis, and 3 ml of absorbing solution are used, the arsenic concentration in milligrams per cubic meter is: 2 X micrograms arsenic from curve 1000 X volume of air sampled in cubic meters It is available commercially or may be built.
Other arrangements of glassware have been used with success, such as a standard borosilicate glass Gutzeit generator connected to a glass delivery tip extending into absorbing solution contained in a Kahn tube. A spectrophotometer, with or without photomultiplier, or any good colorimeter may also be used. Lead acetate solution: Dissolve 10 g of Pb(C2H302)2 3H20 crystals in 100 ml of water. The solution will be slightly turbid as a small amount of the basic salt is formed, but this will not affect its usefulness. The glass wool in the scrubber may be soaked in this solution, drained, and dried, or a few drops may be placed on the glass wool before the evolution of arsine.
Potassium iodide solution: Dissolve 15 g of KI in 100 ml of water.
The solution should be stored in a brown glass bottle.
Zinc: Reagent grade, granular 20 mesh.
Arsenic standard stock solution:
1.320 g arsenic trioxide is dissolved in 10 ml of 40% sodium hydroxide and diluted to 1 liter with distilled water. Various strengths of standard solutions are prepared by further diluting this stock solution with suitable volumes of water.
The water used to make up the reagents, and throughout the analysis, Finally, the liquid should be water-white and fumes of sulfuric acid will be evolved. Further bleaching of the solution may be obtained by cautiously adding 2 ml of a 1:1 mixture of nitric and perchloric acids, and reheating to produce white fumes. Cool slightly and add 5 ml of saturated ammonium oxalate. Heat again until white fumes appear. This oxidation may be completed in less than two hours.
is

# Analysis:
Transfer the oxidized sample with the aid of 25 ml of water to a 100 ml conical flask. Cool to room temperature. Add 5 ml of Detailed procedures to be followed with emphasis on pre cautions to be taken in cleaning up and safe disposal of materials leaked or spilled. This includes proper labeling and disposal of containers containing residues, contaminated absorbants, etc.
(i) Section VIII. Special Protection Information.
Requirements for personal protective equipment, such as respirators, eye protection and protective clothing, and ventilation such as local exhaust (at site of product use or application), general, or other special types.
(j) Section IX. Special Precautions.
Any other general precautionary information such as personal protective equipment for exposure to the thermal decomposition products listed in Section VI, and to particulates formed by abrading a dry coating, such as by a power sanding disc.

# (k)
The signature of the responsible person filling out the data sheet, his address, and the date on which it is filled out.
Barry KG, Herndon EG Jr:
Electrocardiographic changes associated with acute arsenic poisoning. Med Ann D C 31:25 -27, 65-66, 1962 32.
Glazener FS, Ellis JG, Johnson PK: Electrocardiographic findings with arsenic poisoning. Calif Med 109: 1968 33.
Franklin M, Bean WB, Hardin RC: Fowler's solution as an etiologic agent in cirrhosis. Am J Med Sei 219: 1950 34.
Graham JH, Mazzanti GR, Helwig EB: Chemistry of Bowen's disease-Relationship to arsenic. J Invest Dermatol 37:317-32, 1961 35.
Fraser