# I. RECOMMENDATIONS FOR AN INORGANIC ARSENIC STANDARD
The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to arsenic and its inorganic compounds 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 will prevent noncarcinogenic adverse effects of exposure to inorganic arsenic in the workplace air and by skin exposure, and should at the minimum materially reduce the risk of arsenic-induced cancer. 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. "Exposure to arsenic" is defined as exposure at or above 0.002

# Sampling and Analysis
Procedures for sampling, calibration of equipment, and analysis of arsenic samples shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified.

# Section 2 -Medical
Medical surveillance shall be made available and related records kept as specified below for all workers occupationally exposed to arsenic.
(a) Preplacement and annual medical examinations shall include:
(1) Comprehensive preplacement or annual interim work history.
(2) Comprehensive preplacement or annual interim medical history.
x 17" posterior-anterior chest X-ray, giving particular attention to parenchymal and hilar changes.
Complete blood count to include differential. (7) An evaluation of the advisability of the worker's using negative-or positive-pressure respirators.
(b) A periodic sputum cytology examination is recommended for all workers occupationally exposed to inorganic arsenic. The frequency of this procedure should be determined by the responsible medical authority.
(c) Proper medical management shall be provided for workers adversely affected by occupational exposure to inorganic arsenic compounds. The following warning sign shall be affixed in a readily visi ble location at or near entrances to areas in which there is occupational exposure to arsenic.

# ARSENIC DANGER! CANCER CAUSING AGENT
Dust or spray mist may be hazardous to health.
Provide adequate ventilation.
This sign shall be printed both in English and in the predominant language of non-English-speaking workers unless they are otherwise trained and informed of the hazardous area. All illiterate workers shall receive such training.
(a)
Protective Clothing (1) Where there is occupational exposure to inorganic arsenic compounds, protective clothing shall be provided by the employer.
This may include underwear, gloves, coveralls, 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.
(3) 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.

# (b) Respiratory Protection
(1) Engineering controls shall be used wherever feasible to maintain arsenic concentrations below the prescribed limit. Compliance with the permissible exposure limit may not be achieved by the use of respirators except:
(A)
During the time period necessary to install or test the required engineering controls.

# (B)
For nonroutine operations such as a brief exposure to concentrations in excess of the permissible exposure limit as a result of maintenance or repair activities.

# Section 4 -Personal Protective Equipment and Work Clothing (C)
During emergencies when air concentrations of arsenic may exceed the permissible limit.
(2) When a respirator is permitted by paragraph (b)(1) of this Section, it shall be selected and used pursuant to the following requirements:
(A)
The employer shall ensure that no worker is being exposed to arsenic in excess of the environmental limit because of improper respirator selection, fit, use, or maintenance.
(B) A respiratory protection program meeting the requirements of 29 CFR 1910.134 as amended shall be established and enforced by the employer.
(C) The employer shall provide respirators in accordance with Table 1-1 below and shall ensure that the employee uses the respirator provided.
(D) Respiratory protective devices described in Table 1-1 shall be those approved under the provisions of 30 CFR 11 as amended.
(E) The employer shall ensure that respirators are adequately cleaned, and that employees are instructed in the use of respirators assigned to them, and how to test for leakage.
(F) Where an emergency may develop which could result in employee exposure to arsenic, the employer shall provide respiratory protection as listed in Table 1-1. 2) Self-contained breathing apparatus with positive pressure in the facepiece 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 the hazards, relevant symptoms of overexposure, appropriate emergency procedures, and proper conditions and precautions for safe use. Instruction shall include, as a minimum, all information in Appendix III which is applicable to the specific arseniccontaining 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.
Information as required shall be recorded on the "Material Safety Data Sheet" shown in Appendix III or on a similar form approved by the Occupational Safety and Health Administration, US Department of Labor.
(a)
Readily accessible standby rooms under positive air pressure and in which the concentration of arsenic in the air is less than 2.0 fig As/cu m shall be provided where there is occupational exposure to inorganic arsenic.
(b) Arsenic shall be removed from work areas by vacuum cleaning 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.
(c) Waste material shall be disposed of in a manner which will prevent exposure of humans and animals as well as air and water pollution.
(d) Arsenic trichloride shall be handled only in enclosed systems sufficient to prevent skin contact and to prevent worker exposure in excess of the environmental limit.

# (e)
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.
(f) 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.
(g) Exhaust ventilation and enclosure of processes shall be used wherever practicable to control workplace concentrations.

# Section 6 -Work Practices (h)
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.
(i) Due to potential skin irritation associated with respirator use and arsenic dust exposure, workmen shall be permitted to leave the work area every 2 hours to wash their face and obtain a clean respirator. (d) Employees exposed to arsenic shall wash their hands and exposed skin before eating or smoking during the work shift.
(e) No food shall be permitted in areas where arsenic is handled, processed, or stored.
(f) Employees shall not smoke in areas where arsenic is handled, processed, or stored.

# Section 8 -Monitoring and Recordkeeping
Workroom areas shall not be considered to have arsenic exposure if environmental levels, as determined on the basis of a professional indus trial hygiene survey, are less than 2.0 jug As/cu m. Records of these surveys, including the basis for concluding that air levels are less than 2.0 Mg As/cu m, shall be maintained in accordance with Section 8 (e). In workrooms where inorganic arsenic compounds are handled or processed, surveys shall be repeated at least annually and when any process change indicates a need for reevaluation. Requirements set forth below apply to areas in which 1 or more 15-minute breathing zone samples have indicated exposure at or above 2.0 /ug As/cu m.
Employers shall maintain records of environmental exposures to arsenic based upon the following sampling and recording schedules:
(a) In all monitoring, sufficient breathing zone samples shall be collected to characterize the potential exposure of workers at each operation or process.

# (b)
The first environmental sampling shall be completed within 6 months of the promulgation of a standard incorporating these recommendations.
(c) Environmental samples shall be taken within 30 days after first operation of a new process or process changes.
(d) Samples shall be collected at least every 2 months for those work areas in which there is occupational exposure to inorganic arsenic.
(e) Records of all sampling and of medical examinations shall be maintained by the employer or successors thereto for at least 30 years after the individual's employment is terminated. Records shall indicate the type of personal protective devices, if any, in use at the time of sampling.
Records shall be maintained so that exposure information is available for individual employees, and each employee shall be able to obtain information on his own exposure. In the event that the employer ceases business without a successor, records shall be forwarded by When the inorganic arsenic criteria document was first published in January 1974, arsine and lead arsenate were excluded from the provisions of the recommended standard. They are included in these revised recommendations. The inclusion of arsine and other gaseous arsenicals poses some difficulties in that specific work practices are needed, and sampling methods need investigation. However, these difficulties should not be cited as cause for permitting continued exposure to arsine at concentrations above 0.002 mg (2.0 jug) As/cu m. NIOSH is working on these areas and will transmit recommendations directly to the Occupational Safety and Health Administration as soon as possible.
The standard was not designed for the population-at-large, and any extrapolation beyond general occupational exposures is not warranted. It is intended to (1) protect against the noncarcinogenic effects of inorganic arsenicals, (2) materially reduce the risk of arsenic-induced cancer, (3) be measurable by techniques that are valid, reproducible, and available to industry and official agencies, and (4) be attainable with existing technology.

# III. BIOLOGIC EFFECTS OF EXPOSURE

# Extent of Exposure
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 3 and 5, 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 X-l.  Consumption of arsenic trioxide in the United States Is estimated to range between 25,000 and 35,000 tons annually. Of this amount, 6,000-14,000 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 Table X-2.  NIOSH estimates that 1,500,000 workers are potentially exposed to inorganic arsenic, including arsine and lead arsenate.

# Historical Reports
According to Vallee et al,  Paris reported in 1820 that exposure to the arsenical fumes from the copper smelters of Cornwall and Wales occasionally resulted in cancer of the scrotum. Neubauer  reviewed the history of the high mortality due to "mountain disease" among cobalt miners in Schneeberg and Joachimstal in Saxony, and credited Harting and Hesse  with first identifying the condition as lung cancer.

# According to
Neubauer,  arsenic was first believed to be the carcinogen. He concluded that was not the case since Harting and Hesse did not report typical signs of arsenicalism (hyperpigmentation, keratoses, etc). 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. Pigmentation was reportedly most, marked on exposed parts, over pressure areas, and in the normally pigmented areas.
Frost  reviewed the incident, including reports that selenium was also found in the beer.
Tabulating symptoms described in a number of original reports and review articles between 1901 and 1943, he concluded that the incident was not likely due to arsenic alone, since not all symptoms reported in the papers he reviewed could be explained solely by arsenic toxicity, but were consistent with selenium poisoning.
Transverse white striae in the nails (Mees' lines) were first described in 1919  as resulting from the ingestion of a large quantity of arsenic, and were reported to appear approximately 2 months after ingestion. Dinman  considered Mees' lines to be suggestive but not pathognomonic of chronic arsenic poisoning.
According to Buchanan,  18 cases of poisoning due to arsenic trichloride were reported in Britain from 1915 to 1918. In the 1939 case reported by Buchanan, a quantity of liquid arsenic trichloride was spilled over the legs of a processman who was wearing a canister-type respirator.
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 the 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 5 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 1 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, kidneys, 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. (there were no complaints of this type in any of the 3 groups); and peripheral neuropathy, including shooting pains in the extremities, numbness, tingling, or sudden loss of muscular power.
The overall total number of visits per person per year was markedly higher in the packaging group (21.2) than in the manufacturing (9.6) or control group (10.0).  The packaging department employees also had a significantly higher number of visits per person per year for peripheral neuritis complaints (0.13 compared to 0.05 and 0.02).
The authors concluded that these differences were probably due to an unusual number of neurotic individuals in the packaging division since some records contained "page after page of vague and bizarre complaints unexplained by any physical finding." Both the manufacturing and packaging groups had a lower number of visits per person per year for gastrointestinal (0.32 and 0.69) and central nervous system (0.22 and 0.19) complaints than did the control group (0.83 for GI and 0.76 for CNS complaints). However, both exposed groups also had significantly more complaints of hyperkeratosis (0.23 and 0.20 compared to 0.09).
In the manufacturing department, complete blood counts were made at 3-month intervals throughout an individual's employment.  For the 35 employees exposed to arsenic, 323 counts were available. From those workers in the manufacturing department who performed similar tasks but with no arsenic exposure, a control group was randomly selected, providing a total of 221 complete blood counts. There was no significant difference in white, red, neutrophil, or eosinophil counts or in hemoglobin values.

# 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. Arsenic was found in the urine of 2 humans in concen trations of 0.14 and 0.10 /xg As/g of urine (approximately 0.143 and 0.102 mg As/liter, using a specific gravity of 1.024 for conversion).
In the hair of 7 humans, the arsenic level ranged from 0.12 in a 3-year-old to 1.1 /ng As/g of hair in an 80-year-old, with a mean of 0.536 ng As/g. Webster   These authors  considered seafood to be the main source of dietary arsenic. Shellfish in particular elevated the arsenic of test subjects.
In one test, 3 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 4th 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 attacks 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 urinary excretions by individuals were 0.22 and 0.12 mg As/liter.
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 3-4 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 Mees1 lines were present on the nails. There was an erythematous maculopapular 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. The nails contained an average of 9.12 mg As/100 g of nails, with a range of 0.0-42.0 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 eosinophil count was elevated in only 1 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 4. Hematologic abnormalities disappeared within 2-3 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/I00 g of hair (0.009-0.076 mg As/100 g) with an average of 0.051 mg As203/100 g (0.039 mg As/100 g).
In 1943 Zettel  observed 170 soldiers who had been chronically exposed to arsenic in their drinking water. Arsenic was demonstrated in the hair and nails, but the levels were not reported. Most patients had a feeling of weakness, lassitude, dizzy spells, and were easily fatigued. In many cases complaints developed of numbness and "pins and needles" in the limbs, and of cold hands and feet. In about 120 cases the systolic blood pressure at rest was less than 110 mmHg. Electrocardiograms were prepared for 80 patients, 45 of whom displayed a broadened Q-R-S interval. The Q-T was almost always prolonged and, frequently, there was an S-T depression and flattening of the T-wave. Six to eight weeks after the first examination, repeat ECGs were obtained in 47 cases. The Q-R-S broadening initially observed was absent or reduced, and the S-T depression and flattened T-wave were observed less frequently.
Butzengeiger  reported that, of 192 ECGs from vinegrowers suffering chronic arsenic intoxication, 107 (55.7%) were normal, 30 (15.6%)
showed slight changes which alone were insufficient for a definite diagnosis of cardiac damage, and that 55 (28.7%) revealed definite changes.
Of the 55 with definite changes, in 19 cases the possibility existed that the changes were caused by age, arteriosclerosis, or intercurrent disease.
In the remaining 36 cases, no possible causes other than arsenic poisoning were detected. ECG abnormalities included Q-T prolongation and flattened T-wave. Follow-up studies revealed a decline in ECG abnormalities along with the attenuation of other symptoms of arsenic intoxication.
More recently, Barry and Herndon  described characteristic electrocardiographic changes of nonspecific T-wave inversion and pro longation of the Q-Tc interval. In the 3 cases reported, the changes were present on initial ECG's taken shortly after arsenic ingestion at a time when no significant alterations in blood serum electrolytes, serum chemistries, neurologic or respiratory systems were present. In 1 case, an ECG had been performed 3 months before arsenic was ingested and was normal.
This patient, a 21-year-old male, died and post-mortem examination showed "subendocardial hemorrhage and fibrosis with subepicardial petechiae and myocardial perivascular mononuclear infiltration." The ECG changes in the remaining 2 patients regressed coincidentally with clinical recovery, suggesting to the authors an "acute pharmacologic cardiac insult."
Prolongation of the Q-T interval and an abnormal T-wave was reported in 2 cases of chronic and 1 case of acute arsenic intoxication by Glazener et al.  The ECG changes could not be related to disturbances in blood 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 0.0-0.06 mg As/liter as normal.
Graham et al   The cancer deaths were classified into 6 broad site groups. There was no apparent difference between the factory workers and the other 3 occupational groups with respect to cancer of the buccal cavity and pharynx, genitourinary organs, and other or unspecified sites. However, there was an apparent excess among factory workers of deaths due to cancer of respiratory system (31.8% compared to 15.9%) and of the skin (13.6% compared to 1.3%), with a corresponding deficit in deaths due to cancer of the digestive organs and peritoneum (22.7% compared to 58.0%).
Based on factory records and the advice of factory personnel, the deaths among factory workers were subdivided  according to the occupations within the factory. Three groups resulted: chemical workers, engineers and packers, and a general group including builders, printers, watchmen, carters, boxmakers, etc. Of 24 deaths in this last group, 3 (12.5%) were due to cancer, an incidence very similar to that observed in the 3 nonfactory groups. Sixteen of 41 deaths (39.0%) among chemical workers and 3 of 10 deaths (30.0%) among engineers and packers were due to cancer.
Statistically, the cancer incidence in the engineers and packers group did not differ significantly from the control group, but the cancer mortality of the chemical workers was significantly higher (p = 0.047).
All lung cancer and skin cancer deaths (5 and 3, respectively) recorded among factory workers occurred in the chemical worker group. samples from each worker. However, not all workers cooperated, so that there was a total of 58, 32, 22, and 54 urine measurements and 27, 17, 11, and 44 hair samples, respectively, for the 4 groups. The average arsenic excretion was 0.24, 0.10, 0.11, and 0.09 mg As/liter of urine, and 108, 85, 64, and 13 ppm As in hair, respectively. With regard to arsenic both in hair and in urine, exposed workers had significantly higher levels than did the unexposed controls. The 3 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 1-6 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).
Snegireff and Lombard  conducted a statistical study of cancer mortality in the metallurgical industry. From 1922 to 1949, 146 deaths were recorded among the employees at one plant (Plant A) handling large quantities of arsenic trioxide. No mention was made of methods used to trace former and retired employees, so it appears that only deaths among active plant employees were considered. Of the 146 deaths recorded, 18
were due to cancer and 7 of these were ascribed to cancer of the respiratory system. The 18 deaths due to all types of cancer represented a slightly higher proportionate cancer mortality (12.3 cancer deaths per 100 deaths) than observed in the state as a whole (10.0 cancer deaths per 100 deaths). A total of 72 deaths were reported among employees under age 55, and 9 of these were due to cancer of all types (12.5 cancer deaths per 100 deaths). In contrast, the proportionate cancer mortality for this age group in the state as a whole was 6.1 per 100 deaths. The authors showed that both of these increases in proportionate cancer mortality were not statistically significant. This apparently was due to the small sample size.
Also studied was the cancer mortality of Plant Z, comparable to Plant A except that no arsenic was handled.  In Plant Z from 1941-49, 12 of 109 deaths were due to cancer of all types (11.0 cancer deaths per 100 deaths), and 6 of the 12 cancer deaths were due to lung cancer. Compared to the state as a whole in which it was located, (9.6 cancer deaths per 100 deaths), Plant Z had a higher proportionate cancer mortality, but this was not statistically significant.
In the under 55 age group, the mortality due to cancer of all types again was higher (8.3 compared to 5.7 cancer deaths per 100 deaths) in Plant Z, but was not statistically significant.
On the basis of this evidence, they concluded that the handling of arsenic trioxide in industry did not produce significant change in the cancer mortality of plant employees.
By examining only deaths among active plant employees, the authors failed to consider deaths among former employees, including those who retired or changed jobs after long exposure. Therefore, the true cancer mortality may have been higher. Furthermore, the authors did not attempt to compare respiratory cancer mortality in the plants with that in the state as a whole, despite the fact that cancer of the respiratory system in This was in sharp contrast to the total cancer mortality relative to all causes of death when using the same control populations for the 2 plants.
In this case, the cancer death experience showed deficits for Plants A and Z of 4% and 25%, respectively. Thus, even if the absolute figures used were inaccurate, the relative difference demonstrated here indicates that it was the respiratory cancer that required detailed investigation in the original study. A representative control population might also have shown an excess and could have indicated problems both in Plants A and Z. This would then make it inappropriate to compare Plant A to Plant Z, since Plant Z also demonstrated evidence of some type of carcinogen for respiratory cancer.
Using unpublished data supplied by Lull and Wallach, Hueper  reported the cancer mortality in several Montana counties in which copper smelters and mines were operated for many years. In 3 counties in which the major industry was copper smelting and/or mining, the annual lung cancer death rate per 100,000 male population ranged from 46. Urinary arsenic levels were reported  for exposed and nonexposed workers employed in the smelter.
In 147 samples from 124 nonexposed workers, urinary arsenic levels ranged up to 2.07 mg As/liter in 1 case
(the second highest sample reported was 0.7 mg As/liter) and the mean was 0.13 mg As/liter. The average of 835 samples from 348 exposed workers was 0.82 mg As/liter with 7 samples reported as 4.0 mg As/liter or more. There is a distinct difference in the 2 groups, and the urinary level for the "nonexposed" workers is consistent with that reported by Watrous and
McCaughey  for 13 job applicants with no known arsenic exposure.
However, other studies have shown considerably lower normal urinary arsenic levels.
For example, Schrenk and Schreibeis   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. 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 workers 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. areas having the highest average exposure levels for the 5 contaminants.
(The smelter had been subdivided into 12 distinct work areas for the total study.)
The average duration of employment at the smelter for the 17 former workers dying of lung cancer was roughly 29 years.  given for any one of the 10 plants. No mention was made of the extent of exposure to arsenic within these 10 facilities nor was there mention of exactly how many of the workers studied were exposed to arsenic.
Although this study  showed no excess lung cancer, it utilized a relatively insensitive technique (analysis by proportionate mortality ratios), it excluded some of the exposed population (workers who quit work before retirement), and it apparently included many workers who did not have significant arsenic exposure (eg, miners and concentrator workers).
It is possible that a more sensitive method (ie, computation of agespecific mortality rates based on the population at risk and comparison to similar rates in the general population) might detect an increase in cancer mortality not revealed by this study. Should the results of this study be confirmed by a more comprehensive one, they would suggest that inorganic arsenic exposure as experienced by these workers did not cause cancer.
However, no environmental data were presented to describe this exposure, and data from other sources are inadequate.
There are 2 major differences between the Rencher and Carter The distribution of histologic types of bronchogenic carcinoma of the copper miners and other men was very similar. However, the smelter workers had significantly more poorly differentiated epidermoid carcinomas.
The data that were available on smoking habits indicated that there was no difference in the 3 groups with respect to smoking. Newman et al suggested that arsenic was responsible for the increased lung cancer mortality in Anaconda men and women, and they
proposed that an excess of poorly differentiated epidermoid carcinoma might offered no explanation for their observation that the histologic type distribution of bronchogenic carcinoma in Butte women was "surprisingly similar" to that of the smelter workers. They did suggest that the excess cancer mortality in Butte might be attributable to community air pollution arising from the sanding material used on city streets during the winter. Baetjer et al  examined the mortality experience of retirees who had been exposed to arsenic at a Baltimore chemical plant manufacturing arsenical pesticides. Seventeen of 22 deaths among male retirees were due to cancer, compared to 4.43 expected cancer deaths (expected numbers based on age-sex specific proportionate mortality ratios for the city of Baltimore). By site, the ratio of observed to expected (0/E) cancer deaths was 6.71 for respiratory cancer, 3.0 for "lymphatic and hematological cancers" (sometimes referred to as lymphosarcomas), and 1.49 for all other neoplasms.
To conduct a death rate analysis, age-cause-specific death rates were calculated for the population of Baltimore.  These rates were then applied to the person-years at risk of dying for each retiree age group.
Once again, significantly increased cancer mortality was noted for respiratory cancer, with an 0/E ratio of 16.67 (95% confidence limits of 7.14-32.84). Mortality from lymphatic cancer (50.0 0/E ratio, 6.05-180.50 confidence limits) and from all remaining neoplasia (4.65 0/E ratio, 1.26-11.90 confidence limits) were also excessive but the small numbers of deaths in these groups made interpretation difficult.
Ott et al  compared the proportionate mortality experience of 173 decedents who had been primarily exposed to lead and calcium arsenate with that of 1,809 decedents without arsenic exposure. As a percentage of total deaths, cancer of the respiratory system was significantly higher as a cause of death in the exposed group (16,2%) than in the controls (5.7%).
Cancer of the lymphatic and hematopoietic tissues (described as not including leukemia) was also significantly higher in the exposed group (3.5% compared to 1.4% expected). Specifically, the 6 cases of lymphoma were classified on death certificates as 1 lymphoblastoma, 1 reticulum cell sarcoma, and 4 cases of Hodgkin's disease.
To supplement this proportionate analysis, the authors also examined the mortality in a cohort of 603 chemical workers with at least 1 month of work in the arsenic production areas.  Person-years lived by the cohort were used to compute the expected number of deaths by cause, based on the US white male mortality. Total deaths were lower than expected (0/E ratio of 0.84), and this was consistent with overall mortality at this company location where mortality from all causes varied from 60-85% of US mortality. However, mortality due to respiratory cancer (0/E ratio of 3.45) and cancer of the lymphatic and hematopoietic tissues except leukemia (0/E ratio of 3.85) was significantly higher than expected in the cohort of exposed workers. Using these estimates and work histories, the authors calculated arsenic dosages for the workers included in the proportionate analysis and in the retrospective cohort analysis. In both cases, an apparent dose-response relationship was shown between arsenic exposure and respiratory cancer mortality. The authors estimated the 0/E ratio for respiratory cancer would be 7:1 for individuals exposed for more than 8 years at an "equivalent level of 1 mg/cu m arsenic." The authors reported they could find "no common denominator," other than arsenic, to explain the observed excess cancer mortality.

# Blejer and
Wagner  used the total arsenic dosages as published by Ott et al  to calculate what the daily 8-hour time-weighted average (TWA) exposure would have been if the total arsenic dosages were taken to represent those inhaled by workers over a 40-year working life. As shown in Table III-4, these calculations suggest that respiratory cancer mortality was twice the expected at a dosage equivalent to exposure for 40 years at 3.0 ig As/cu m on an 8-hour TWA basis, while the 0/E ratio was 0.6 at the equivalent to 1.0 jug As/cu m.

# 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  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 1 of 2 concentrations. In the 1 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 nontoxlc 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.
Ginsburg and Lotspeich  investigated the mechanisms of renal arsenate excretion in the dog and reported similarities between arsenate and phosphate excretion. Net tubular reabsorption of arsenate was observed, inhibited by increased plasma phosphate concentrations. The authors interpreted this as indicating a competitive interaction between these ions. Reduction of arsenate to arsenite was reported, but whether this occurred in the urine, either in the lumen of the kidney tubules or in the bladder, or intracellularly could not be determined. Ginsburg  later reported that reduction to arsenite occurred intracellularly.
Arsenite then diffused across both luminal and antiluminal faces of the tubular cell, resulting in higher plasma arsenite levels in renal venous than in renal arterial blood. 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 3 groups of female albino rats were exposed 24 hours a day for 3 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 1 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 2 highest exposure groups, and was still apparent 1 month after exposure in the highest exposure group. Some accumulation of arsenic, mostly in the lungs and liver, was shown at the end of the exposure period in the 2 highest exposure groups. In the most heavily exposed animals these organs retained a high arsenic content 1 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 shriveling of neurons in the middle pyramidal tract.  There was an accumulation of leukocytic exudate in the bronchi, 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.
One difficulty with this study  is that, as grooming animals, the rats may have ingested arsenic trioxide from the fur. 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 1 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 1 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 3 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.
Among 35 male and 20 female untreated controls, 3 of 20 deaths in the males and none of 16 deaths in the females were due to leukemia. Test animals were given injections of a 0.005% aqueous solution of the "sodium salt"
(the valence of the arsenic was not specified) 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) that received no additional arsenic treatment.
The leukemia rate was further increased when arsenic was injected subcutaneously into the offspring themselves (41 of 92 deaths).
In 20 females receiving 20 once-weekly intravenous injections of 0. At 1850 ppm lead arsenate caused intra-and extrahepatic bile-duct lesions, significantly reduced weight gain, and caused increased mortality.
The only blood changes that seemed relevant were observed in this group-reduced hemoglobin, packed cell volume, and erythrocyte count. No difference was observed either in the tumor incidence of the groups or in the times at which tumors were detected.
No carcinogenic action was attributable to sodium arsenate and DENA, alone or in combination, but in group 2 an adenoma in the renal cortex and a bile duct carcinoma were found.
The authors suggested that these tumors might be "indicative of a very weak carcinogenic action" by lead arsenate, but they also recognized that no definite conclusion can be drawn from these data.

# Correlation of Exposure and Effect
There are no environmental data in the reports by Holmqvist  and Birmingham et al  on the effects of arsenic on the skin, but a doseresponse relationship is implied in both. Despite sensitization problems, Holmqvist  reported that the incidence of dermatitis was highest in areas with heaviest arsenic exposure. Similarly, Birmingham et al  reported no dermatitis among high school students who attended school elsewhere, but younger children attending school in the mining camp did have dermatitis. Urinary arsenic levels of the elementary school children were said to "compare favorably" with those reported by Pinto and McGill  for exposed smelter workers. Thus, dermatitis apparently was seen in association with a urinary excretion of 0.8 mg As/liter.
In a study  of an English sheep-dip factory, chemical workers were shown to have increased cancer mortality while the other 2 occupa tional groups did not.
The plant was the subject of an environmentalclinical survey  during which air samples were collected on 5 occasions from 4 work areas: in the packing room, drying room, sieving room, and near the kibbler operator. Additionally, on 1 occasion 7 samples were collected on the mixing platform, by and between the kneading machine, while loading and unloading a kiln, and during the blending of ingredients.
Neither in the epidemiological  nor in the environmental  portion of the study was the "chemical worker" grouping defined or associated with particular jobs in the factory. However, based on the job titles included in the other 2 groups-packers, engineers (also called maintenance workers ), builders, printers, watchmen, etc-it appears that those workers in the drying room and sieving room, operating the kibbler, kneading, and blending machines, and the kilns would be classified as "chemical workers" A study of a large smelter population was reported in 1969 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. Atomic absorption spectrophotometry is the recommended analytical method because, in addition to possessing the required sensitivity, it is more widely known than alternative methods are at this time.

# 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 are 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 mg 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 before sea food was recognized as a factor. Since no record of diet had been kept, these unusually high values could not be excluded (the 3 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, 3 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.
Pinto and McGill  analyzed the urine of 348 men (845 spot samples) occupationally exposed to arsenic trioxide and reported a mean level of 0.82 mg As/liter. The median value was 0.58 mg As/liter, and 27.3% of the samples exceeded 1.0 mg As/liter. One hundred forty-seven urine samples from 124 active smelter employees considered to have no arsenic exposure averaged 0.13 mg As/liter. The 3 highest values were 0.53, 0.70, and 2.06 mg As/liter, but 88% of the samples were below 0.2 mg As/liter. Although it was stated that among the exposed workers there was only 1 dubious case of mild systemic arsenic poisoning, there were several cases (at least 17) of acute arsenical dermatitis. Over a 6-day period, 16 of these had average urine arsenic levels, during or following British Anti-Lewisite (BAL) therapy, ranging from 0.30 to 0.93 mg As/liter. One individual with severe facial dermatitis of rapid onset received BAL every 6 hours for 4 days, but excreted an average of only 0.2 mg As/liter. It was surmised that this man was hypersensitive or allergic to arsenic. One individual who declined BAL therapy had urinary arsenic levels ranging from 3.15 to 5.76 mg As/liter over a 2-day period. According to these authors,  individuals may show urinary arsenic levels in spot samples as high as 4 or 5 mg As/liter, without any evidence of systemic arsenic poisoning.
In an English sheep-dip factory,  urinary arsenic levels were determined for workers exposed to mixed arsenic trioxide and sodium arsen-ite dusts, and for unexposed controls. The urinalyses of exposed personnel were repeated after an interval of 6 months.
The mean urinary arsenic level for 54 controls was 0.085 mg As/liter, and in 58 determinations made on chemical workers (the most heavily exposed group), the mean was 0.231 mg As/liter (computed from the data given in Tables 6 and 7 by Perry et al ). The 3 highest levels recorded in the exposed group were equivalent 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 above 4.0 mg As/liter have been reported  without apparent adverse effects.
On the other hand, signs of mild systemic poisoning have been reported  in a worker excreting only 0.76 mg As/liter. This wide variability in urinary arsenic levels, even in an apparently unexposed In his discussion of the 0.15 mg As/cu m standard, Cook stated that "On the basis of long experience  involving many occupational exposures, at least cne large concern considers it permissible to increase the limit to 5. mg. per cubic meter."
In 1947 the American Conference of Governmental Industrial Hygienists (ACGIH) adopted a MAC for arsenic of 0.1 mg/cu m,  but the following year this was raised to a Threshold Limit Value (TLV) of 0.5 mg As/cu m.
 The ACGIH gave no explanation for the change, but Pinto, commenting in a July 1972 written communication to ANSI on the 0.5 mg As/cu m standard, stated that arsenic trioxide was considered to be the primary arsenic compound to which there was industrial exposure, and the 0.5 mg
As/cu m level was suggested as a safe concentration of arsenic trioxide, with "safe concentration" meaning that "it would not cause incapacitating dermatitis in a few hours." Whether the change from a MAC to a TLV constituted a change from a ceiling of 0.1 mg/cu m to a time-weighted average of 0.5 mg/cu m is not clear. If that was the case and one applies the excursion factor of 3 presently recommended by the ACGIH  for TLVs in the 0.0-1.0 mg/cu m range, this change constituted a 15-fold increase.
The present TLV recommended by the ACGIH is 0.5 mg As/cu m for "arsenic and compounds,"  but in 1974 a notice of intended change to 0.25 mg As/cu m was published,  and the ACGIH Plenary Committee has recently proposed  that the 1975 TLV book list inorganic arsenic compounds in In January, 1974, NIOSH transmitted to the Department of Labor a recommended standard for occupational exposure to inorganic arsenic that included an environmental limit of 0.05 mg As/cu m. Arsine and lead arsenate were excluded from the provisions of that recommended standard.
Additional information that was published or made available after that document was published led to a review of the NIOSH recommendations, and in November, 1974, NIOSH transmitted a memorandum to the Department of Labor in which modified recommendations were made for an inorganic arsenic standard. Additional significant information has developed since late 1974, and, along with the earlier reports, has been the object of continuing review and evaluation within NIOSH. The rapid development of new information and the consequent alterations in NIOSH recommendations have made this new criteria document necessary.

# Basis for Recommended Environmental Standard
A number of signs and symptoms are associated with arsenic poisoning.
When ingested, arsenic compounds can cause nausea, vomiting, and diarrhea within a few hours,  although in at least one animal study  with arsenic trioxide, much of the gastrointestinal irritation was attributed to impurities. Dermatitis may be observed  after chronic ingestion, but the typical signs of chronic arsenicalism are hyperpigmentation and hyperkeratosis, especially on the palmar and plantar surfaces,  and peripheral neuropathy  in a glove and stocking distribution with prickly sensations  and loss of distal proprioception and deep tendon reflexes.  Changes in the ECG have been reported after both acute  and chronic  intoxication, although in at least one report  of severe chronic arsenicalism, the patient's ECG was normal.
ECG changes that were observed  regressed after arsenic exposure ceased. Anemia and leukopenia were reported  in cases of chronic intoxication, but these changes also regressed after arsenic ingestion ended. Effects on the liver include cirrhosis after prolonged use of Fowler's solution,  and, in animal studies, marked enlargement of the bile duct  and fatty degeneration of the liver.  Skin cancer has long been considered  a consequence of arsenic exposure, but multiple cancers of the viscera have also been reported.  However, the association too often was made because a cancer patient exhibited hyperpigmentation and hyperkeratoses. On this basis, cases were included both in Neubauer's review  in which 147 cases were collected and in the cases reported by Sommers and McManus  despite the fact that in some cases there was no known arsenic exposure.
No reports were found of occupational exposure to arsenic compounds resulting in nausea, vomiting, diarrhea, or peripheral neuropathy. Occu pational exposures have been reported to cause hyperpigmentation,  palmar and plantar hyperkeratoses,  warts,  contact dermatitis and sensitization,  ulceration and perforation of the nasal septum,  and conjunctivitis.  Reversible ECG changes  and severely reduced peripheral circulation resulting in gangrene of the fingers and toes  have been reported. Cirrhosis of the liver has been observed,  and one epidemiological study  of a smelter population reported significantly increased mortality due both to cirrhosis of the liver and to cardiovascular disease.
Another study  of mortality among smelter workers found that cardiovascular mortality was not significantly increased in workers exposed to arsenic.
Mortality studies of orchardists exposed to lead arsenate spray  and of copper smelter workers  found no excessive cancer mortality. However, as discussed in the section on Epidemiologic Studies, the conclusions in each of these reports are questionable.
Other studies have reported cancer of the skin,  lung,  lymphatic system,   conjunctivitis,  ECG changes,  disturbed peripheral circulation,  or cirrhosis of the liver.  The question of air levels was approached only by Pinto and McGill,  who considered dust-in-air measurements to be of limited value for predicting skin reactions, and by Ott et al  who estimated total dosages of arsenic and showed an apparent dose-response relationship for respiratory cancer.
ECG changes reported after nonoccupational  and occupa tional  exposure to arsenic have apparently been reversible. One epi demiological study  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  many of the vineyard workers were said to drink 2 liters or more of wine daily. A recent epidemiological study  of an American smelter population found increased mortality due to cirrhosis of the liver, but the increase apparently was not related to length of exposure. Animal studies have reported liver damage after ingestion of either sodium arsenite or arsenate  and after inhalation of arsenic trioxide.  Thus the potential for liver damage seems real, but it is not clear whether occupational exposures have actually resulted in damage, and if so, at what concentration.
Two mortality studies  of smelter populations have reported that observed cancer mortality exceeded the expected mortality but not significantly.
A third paper  reported no excess cancer mortality in the smelter population studied. These authors concluded that workers exposed to arsenic did not experience increased cancer mortality, but that conclusion is open to question. In the Snegireff and Lombard study,  the authors examined and discussed only overall cancer mortality. However, according to a comparison made by NIOSH, respiratory cancer mortality as a proportion of total cancer deaths was 5.7 times expected in the plant at which arsenic trioxide was handled and 6.5 times expected in the comparison plant at which arsenic was not handled. Thus, both plants apparently had increased respiratory cancer mortality, although overall cancer mortality was not significantly increased. respiratory cancer mortality in the smelter population they studied, and they showed that the cancer risk increased with the degree of arsenic exposure as well as with the length of exposure.
As reported by Hill and Faning,  the cancer mortality of chemical workers in an English sheep-dip factory was significantly increased. The small numbers involved made firm conclusions difficult, but the authors suggested that the excess could be attributed to increased lung and skin cancer mortality.
A definite excess in respiratory cancer mortality was reported by Baetjer et al  and by Ott et al  among American workers exposed to arsenates and some arsenites in pesticide plants. These American pesticide plant employees were also shown to have experienced excessive lymphatic cancer mortality.  These studies  strongly implicate arsenic as an occupational carcinogen. However, the relationship is obscured because, in the smelting industry, the workers were exposed to a variety of substances other than arsenic, one of which was sulfur dioxide.
In the Lee and Fraumeni report,  lung , cancer mortality increased with increasing arsenic exposure; but generally the sulfur dioxide levels also increased with the arsenic levels. It was not possible to examine the mortality of a subgroup exposed only to arsenic or only to sulfur dioxide, so a role by sulfur dioxide or some other substance cannot be ruled out in the smelting industry.
However, the involvement of arsenic cannot be denied.
Furthermore, there was no suggestion of sulfur dioxide exposure in the sheep-dip factory  or in the American pesticide plants,  but cancer mortality still was significantly increased.  Even if contact dermatitis and systemic toxicity were the only bases for establishing a standard, it is evident that the existing Federal standard of 0.5 mg As/cu m is too high because, according to Pinto in a July 1972 written communication to ANSI, it was originally established to prevent "incapacitating dermatitis in a few hours," clearly an inadequate basis from present-day considerations. Moreover, recent reports  undeniably associate occupational exposure to inorganic arsenic with increased cancer mortality.
Although their environmental data were scanty, Ott et al  calculated total arsenic dosages received by exposed workers and showed an apparent dose-response relationship for respiratory cancer mortality.
Using these data, Blejer and Wagner  calculated 8-hour TWAs that would produce the same dosages after a 40-year working life (Table III -4). For the group with the lowest total arsenic dosage, the 0/E ratio for respiratory cancer was 0. This conclusion is supported by the reports of Ott et al  and Blejer and Wagner.  In the absence of information for a safe level of exposure to a carcinogen such as inorganic arsenic, protection of the worker should be effected by requiring that airborne concentrations not exceed minimally detectable levels. Inorganic arsenic, however, presents a serious complication by its ubiquity in the environment. NIOSH recommends that worker exposure to inorganic arsenic be controlled to prevent exposure in excess of 2.0 Mg As/cu m of air as determined by a 15-minute sampling period. This short-term limit is intended to achieve the greatest practicable reduction in worker exposure while avoiding spurious sampling results produced by natural background concentrations of inorganic arsenic. Although there may be enforcement problems in heavily polluted areas, background levels in such places cannot be considered natural, and may be unsafe. Inorganic arsenic compounds can have a direct effect on the skin or may be absorbed through the skin. They also may be absorbed from the lungs, from the tracheobronchial tree, and from the gastrointestinal tract (most nonrespirable particles deposited in the upper respiratory tract are ingested). Since a toxicologic response can be elicited by arsenic absorbed by any of these routes, the recommended environmental limit is intended to apply to total dust samples, rather than only the respirable fraction.
Since the studies by Baetjer et al  and Ott et al  demon strate an association between lymphatic cancer and inorganic arsenic exposure, chest X-rays should be examined for changes that can be suggestive of lymphoma as well as lung cancer. Two additional provisions that can be indicative of lymphoma are also recommended: palpation of the superficial lymph nodes and a complete blood count with differential.
Although  (e) For 20 or fewer samples, 3 blank filters carried in closed cassettes to the sampling site shall be provided to the analytical laboratory for determination of the background correction which must be applied to the analytical results. One additional blank shall be provided for each 10 samples after the first 20.

# 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 for 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-or 2-liter buret or wet test meter is recommended, although other standard calibrating instruments such as spirometer, Marriott's bottle, or dry-gas meter can be used.
Instructions for calibration with the soapbubble meter follow. If another calibration device is selected, equivalent procedures should be used.
The calibration setup for personal sampling pumps with a cellulose membrane filter is shown in Figure X-l. Since the flowrate given by a pump is dependent on the pressure drop of the sampling device, in this case a membrane filter, the pump must be calibrated while operating with a representative filter and backup pad in line.
(1) While the pump is running, the voltage of the pump battery is checked with a voltmeter to assure adequate voltage for calibration. The battery is charged if necessary.
(2) Place the cellulose membrane filter with backup pad in the filter cassette.
The sampling train is assembled as shown in Figure X-l.
The pump is turned on and the inside of the soapbubble meter is moistened by immersing the buret in the soap solution and drawing bubbles up the inside until they are able to travel the entire buret length without bursting.
The pump rotameter is adjusted to provide a flowrate of 2.0 liters/min.
The water manometer is checked to insure that the pressure drop across the sampling train does not exceed 13 inches of water at 2 liters/min.
The procedure in (7) above is repeated at least 3 times, the results averaged, and the flowrate calculated by dividing the volume between the preselected marks by the time required for the soapbubble to traverse the distance. expected to be greater.
The accuracy of the method has not been determined at this time.

# ADVANTAGES AND DISADVANTAGES OF THE METHOD
This method has the advantage of being free of interference by antimony. It is somewhat faster, and several times as sensitive as the colorimetric method for arsenic. The disadvantages include the requirement of specialized equipment and the use of rather large volumes of expensive gases. This analytical procedure does not distinguish between pentavalent and trivalent arsenic compounds. Specialized research methods which are not widely used reportedly can distinguish between these valence states. Construct a calibration curve by pipetting 5 ml of each of the working standards into arsine generators and proceeding with the analysis.
A calibration curve of absorbance versus micrograms of arsenic is plotted and used for the determination of arsenic content of the samples.

# CALCULATIONS (a) Urine Samples
The concentration of arsenic in the urine sample can be expressed as mg As/liter of urine.
mg As/liter = m % As (from calibration curve) ml of urine The use of a specific gravity correction factor to normalize values to 1.024, the average specific gravity of urine, has been proposed. [92-
The following correction is recommended. Specific gravities less than 1.010 are unreliable and these samples should be discarded.
corrected mg As/liter = mg As/liter X _______(1.024-1.000)________ (specific gravity -1.000) Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature.
Where possible, avoid using common names and general class names such as "aromatic amine,"
"safety solvent," or "aliphatic hydrocarbon" when the specific name is known.
The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets.
Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, ie, "100 ppm LC50-oral-rat," "25 mg/cu m LD50-skin-rabbit," "75 ppm LC man," or "permissible exposure from 29 CFR The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a time-weighted average (TWA) concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved.
Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be:
Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, mild irritation and possibly some blistering.
Eye Contact-some pain and mild transient irritation; no corneal scarring.
"Emergency and First Aid Procedures" should be written in lay language and should primarily represent first aid treatment that could be provided by paramedical personnel or individuals trained in first aid.
Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers. Respirators shall be specified as to type and NIOSH or US Bureau of Mines approval class, ie, "Supplied air," "Organic vapor canister," "Suitable for dusts not more toxic than lead," etc. Protective equipment must be specified as to type and materials of construction.

# D E P A R T M E N T O F H E A L T H . E D U C A T IO N . A N D W E L F A R E P U B L IC H E ALTH S E R V IC E C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E
available. Working standards are made by diluting the stock solution.
(j)
Gases. Hydrogen, electrolytic grade. Argon, high purity.

# PROCEDURE (a) Cleaning Equipment
All glassware must be cleaned with a detergent solution followed by both tap water and distilled water rinses. Then the glassware is cleaned with hot concentrated nitric acid and thoroughly rinsed with tap water followed by distilled water.