Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure levels that are safe for various periods of employment, including but not limited to the exposures at which no worker will suffer diminished health, functional capacity, or life expectancy because of his or her work experience. Criteria documents contain a critical review of the scientific and technical information about the prevalence of hazards, the existence of safety and health risks, and the adequacy of control m eth ods. By means of criteria documents, NIOSH communicates these recommended standards to regulatory agencies, including the Occupational Safety and Health Administration (OSHA), health professionals in academic institutions, industry, organized labor, public interest groups, and others in the occupational safety and health community. This criteria document is derived from the NIOSH evaluation of critical health effects studies of occupational exposure to hexavalent chromium (Cr) compounds. It provides recommenda tions for controlling workplace exposures including a revised recommended exposure limit (REL) derived using current quantitative risk assessment methodology on human health effects data. This document supersedes the 1975 Criteria for a Recommended Standard: Occupational Exposure to Chromium(VI) and NIOSH Testimony to OSHA on the Proposed Rule on Occupational Exposure to Hexavalent Chromium [NIOSH 1975a[NIOSH  , 2005a. Cr(VI) compounds include a large group of chemicals with varying chemical properties, uses, and workplace exposures. Their properties include corrosion-resistance, durability, and hardness. So dium dichromate is the most common chromium chemical from which other Cr(VI) compounds may be produced. Materials containing Cr(VI) include various paint and prim er pigments, graphic art supplies, fungicides, corrosion inhibitors, and wood preservatives. Some of the industries in which the largest numbers of workers are exposed to high concentrations of Cr(VI) compounds include electroplating, welding, and painting. An estimated 558,000 U.S. workers are exposed to airborne Cr(VI) compounds in the workplace. Cr(VI) is a well-established occupational carcinogen associated with lung cancer and nasal and sinus cancer. NIOSH considers all Cr(VI) compounds to be occupational carcinogens. NIOSH rec ommends that airborne exposure to all Cr(VI) compounds be limited to a concentration of 0.2 Cr(VI)/m3 for an 8-hr time-weighted average (TWA) exposure, during a 40-hr workweek. The REL is intended to reduce workers' risk of lung cancer associated with occupational exposure to Cr(VI) compounds over a 45-year working lifetime. It is expected that reducing airborne workplace expo sures to Cr(VI) will also reduce the nonmalignant respiratory effects of Cr(VI) compounds, includ ing irritated, ulcerated, or perforated nasal septa and other potential adverse health effects. Becauseof the residual risk of lung cancer at the REL, NIOSH further recommends that continued efforts be made to reduce Cr(VI) exposures to below the REL. A hierarchy of controls, including elimina tion, substitution, engineering controls, administrative controls, and the use of personal protective equipment, should be followed to control workplace exposures.# Executive Summary
In this criteria document, the National Institute for Occupational Safety and Health (NIOSH) re views the critical health effects studies of hexavalent chromium (Cr ) compounds in order to update its assessment of the potential health effects of occupational exposure to Cr(VI) compounds and its recommendations to prevent and control these workplace exposures. NIOSH reviews the following aspects of workplace exposure to Cr(VI) compounds: the potential for exposures (Chap ter 2), analytical methods and considerations (Chapter 3), human health effects (Chapter 4), ex perimental studies (Chapter 5), and quantitative risk assessments (Chapter 6). Based on evalua tion of this information, NIOSH provides recommendations for a revised recommended exposure limit (REL) for Cr(VI) compounds (Chapter 7) and other recommendations for risk management (Chapter 8).
This criteria document supersedes previous NIOSH Cr(VI) policy statements, including the 1975 NIOSH Criteria for a Recommended Standard: Occupational Exposure to Chromium(VI) and NIOSH Testimony to OSHA on the Proposed Rule on Occupational Exposure to Hexavalent Chromium .
Cr(VI) compounds include a large group of chemicals with varying chemical properties, uses, and workplace exposures. Their properties include corrosion-resistance, durability, and hardness. Workers may be exposed to airborne Cr(VI) when these compounds are manufactured from oth er forms of Cr (e.g., the production of chromates from chromite ore); when products containing Cr(VI) are used to manufacture other products (e.g., chromate-containing paints, electroplating); or when products containing other forms of Cr are used in processes that result in the formation of Cr(VI) as a by-product (e.g., welding). In the marketplace, the most prevalent materials that con tain chromium are chromite ore, chromium chemicals, ferroalloys, and metal. Sodium dichromate is the most common chromium chemical from which other Cr(VI) compounds may be produced. Cr(VI) compounds commonly manufactured include sodium dichromate, sodium chromate, p o tassium dichromate, potassium chromate, ammonium dichromate, and Cr(VI) oxide. Other m an ufactured materials containing Cr(VI) include various paint and prim er pigments, graphic arts supplies, fungicides, and corrosion inhibitors.
An estimated 558,000 U.S. workers are exposed to airborne Cr(VI) compounds in the workplace. Some of the industries in which the largest numbers of workers are exposed to high concentra tions of airborne Cr(VI) compounds include electroplating, welding, and painting. An estimated 1,045,500 U.S. workers have dermal exposure to Cr(VI) in cement, primarily in the construction industry.
Cr(VI) is a well-established occupational carcinogen associated with lung cancer and nasal and sinus cancer. NIOSH considers all Cr(VI) compounds to be occupational carcinogens  compounds as encountered in the chromate production, chromate pigment production and chromium plating industries" (i.e., IARC category "Group 1" carcinogen) . Cr(VI) compounds were reaf firmed as an IARC Group 1 carcinogen (lung) in 2009 . The National Toxicology Program (NTP) identified Cr(VI) compounds as carcinogens in its first annual report on carcinogens in 1980 . Nonmalignant respiratory effects of Cr(VI) compounds in clude irritated, ulcerated, or perforated nasal septa. Other adverse health effects, including repro ductive and developmental effects, have been reviewed by other government agencies . Studies of the Baltimore and Painesville cohorts of chromate production workers  provide the best information for predicting Cr(VI) cancer risks because of the quality of the exposure estimation, large amount of worker data available for analysis, extent of ex posure, and years of follow-up . NIOSH selected the Baltimore cohort  for analysis because it has a greater num ber of lung cancer deaths, better smoking histories, and a more comprehensive retrospective exposure archive. The NIOSH risk assessment estimates an excess lifetime risk of lung cancer death of 6 per 1,000 workers at 1 |ig Cr(V I)/m 3 (the previ ous REL) and approximately 1 per 1,000 workers at 0.2 ^g Cr(VI)/m3 (the revised REL) . The basis for the previous REL for carcinogenic Cr(VI) compounds was the quantitative limitation of the analytical m ethod available in 1975.
Based on the results of the NIOSH quantitative risk assessment , NIOSH recom mends that airborne exposure to all Cr(VI) compounds be limited to a concentration of 0.2 Cr(VI)/m3 for an 8-hr TWA exposure, during a 40-hr workweek. The REL is intended to reduce workers' risk of lung cancer associated with occupational exposure to Cr(VI) compounds over a 45-year working lifetime. It is expected that reducing airborne workplace exposures to Cr(VI) will also reduce the nonmalignant respiratory effects of Cr(VI) compounds, including irritated, ulcer ated, or perforated nasal septa and other potential adverse health effects. Because of the residual risk of lung cancer at the REL, NIOSH recommends that continued efforts be made to reduce ex posures to Cr(VI) compounds below the REL.
The available scientific evidence supports the inclusion of all Cr(VI) compounds into this recom mendation. Cr(VI) compounds studied have demonstrated their carcinogenic potential in animal, in vitro, or human studies . Molecular toxicology studies provide additional support for classifying Cr(VI) compounds as occupational carcinogens.
The NIOSH REL is a health-based recommendation derived from the results of the NIOSH quan titative risk assessment conducted on hum an health effects data. Additional considerations include analytical feasibility and the achievability of engineering controls. NIOSH M ethod 7605, OSHA M ethod ID-215, and international consensus standard analytical methods can quantitatively assess worker exposure to Cr(VI) at the REL. Based on a qualitative assessment of workplace exposure data, NIOSH acknowledges that Cr(VI) exposures below the REL can be achieved in some work places using existing technologies but are more difficult to control in others . Some operations, including hard chromium electroplating, chromate-paint spray application, atomized-alloy spray-coating, and welding may have difficulty in consistently achieving exposures at or below the REL by means of engineering controls and work practices . The extensive analysis of workplace exposures conducted for the OSHA rule-making process supports the NIOSH assessment that the REL is achievable in some workplaces but difficult to achieve in others .
A hierarchy of controls, including elimination, substitution, engineering controls, administrative controls, and the use of personal protective equipment, should be followed to control workplace exposures. The REL is intended to promote the proper use of existing control technologies and to encourage the research and development of new control technologies where needed, in order to control workplace Cr(VI) exposures.
At this time, there are insufficient data to conduct a quantitative risk assessment for workers ex posed to Cr(VI), other than chromate production workers or specific Cr(VI) compounds other than sodium dichromate. However, epidemiologic studies demonstrate that the health effects of airborne exposure to Cr(VI) are similar across workplaces and industries (see Chapter 4). There fore, the results of the NIOSH quantitative risk assessment conducted on chromate production workers  are used as the basis of the REL for all workplace exposures to Cr(VI) compounds.
The prim ary focus of this document is preventing workplace airborne exposure to Cr(VI) com pounds to reduce workers' risk of lung cancer. However, NIOSH also recommends that dermal exposure to Cr(VI) compounds be prevented in the workplace to reduce adverse dermal effects including skin irritation, skin ulcers, skin sensitization, and allergic contact dermatitis.
NIOSH recommends that employers implement measures to protect the health of workers exposed to Cr(VI) compounds under a comprehensive safety and health program, including hazard com munication, respiratory protection programs, smoking cessation, and medical monitoring. These elements, in combination with efforts to maintain airborne Cr(VI) concentrations below the REL and prevent dermal contact with Cr(VI) compounds, will further protect the health of workers.

# Contents

# Introduction 1.1 Purpose and Scope
This criteria document describes the most recent NIOSH scientific evaluation of occupational ex posure to hexavalent chromium (Cr ) com pounds, including the justification for a revised recommended exposure limit (REL) derived us ing current quantitative risk assessment m eth odology on human health effects data. This cri teria document focuses on the relevant critical literature published since the 1975 Criteria for a Recommended Standard: Occupational Exposure to Chromium(VI) . The policies and recommendations in this document pro vide updates to the NIOSH Testimony on the OSHA Proposed Rule on Occupational Exposure to Hexavalent Chromium and the correspond ing NIOSH Post-Hearing Comments . This final document incorporates the NIOSH response to peer, stakeholder, and pub lic review comments received during the exter nal review process.

# History of NIOSH Cr(VI) Policy
In the 1973 Criteria for a Recommended Stan dard: Occupational Exposure to Chromic Acid, NIOSH recommended that the federal standard for chromic acid, 0.1 mg chromium trioxide/ m3, as a 15-minute ceiling concentration, be retained because of reports of nasal ulceration occurring at concentrations only slightly above this concentration . In addition, NIOSH recom m ended 0.05 mg chrom ium trioxide/m 3 time-weighted average (TWA) for an 8-hour workday, 40-hour work week, to protect against possible chronic effects, includ ing lung cancer and liver damage.
In the 1975 Criteria for a Recommended Stan dard: Occupational Exposure to Chromium(VI), NIOSH supported two distinct recommended standards for Cr(VI) compounds . Some Cr(VI) compounds were consid ered noncarcinogenic at that time, including the chromates and bichromates of hydrogen, lithium, sodium, potassium, rubidium, cesi um, and ammonium, and chromic acid anhy dride. These Cr(VI) compounds are relatively soluble in water. It was recommended that a 10-hr TWA limit of 25 |ig Cr(VI)/m 3 and a 15-minute ceiling limit of 50 |ig Cr(VI)/m 3 be applied to these Cr(VI) compounds.
All other Cr(VI) compounds were considered carcinogenic . These Cr(VI) compounds are relatively insoluble in water. At that time, NIOSH subscribed to a carcino gen policy that called for "no detectable expo sure levels for proven carcinogenic substances" . The basis for the REL for car cinogenic Cr(VI) compounds, 1 |ig Cr(VI)/m3 TWA, was the quantitative limitation of the an alytical m ethod available at that time for mea suring workplace exposures to Cr(VI).
NIOSH revised its policy on Cr(VI) com pounds in the NIOSH Testimony on the OSHA Proposed Rule on Air Contaminants . NIOSH testified that although insol uble Cr(VI) compounds had previously been demonstrated to be carcinogenic, there was now sufficient evidence that soluble Cr(VI) com pounds were also carcinogenic. NIOSH recom mended that all Cr(VI) compounds, whether soluble or insoluble in water, be classified as po tential occupational carcinogens based on the OSHA carcinogen policy. NIOSH also recom mended the adoption of the most protective of the available standards, the NIOSH RELs. Con sequently the REL of 1 |ig Cr(VI)/m3 TWA was adopted by NIOSH for all Cr(VI) compounds.
NIOSH reaffirmed its policy that all Cr(VI) compounds be classified as occupational car cinogens in the NIOSH Comments on the OSHA Request for Information on Occupation al Exposure to Hexavalent Chromium and the NIOSH Testimony on the OSHA Proposed Rule on Occupational Exposure to Hexavalent Chro mium [NIOSH 2002[NIOSH , 2005a. Other NIOSH Cr(VI) policies were reaffirmed or updated at that time [NIOSH 2002[NIOSH , 2005a. This criteria document updates the NIOSH Cr(VI) policies, including the revised REL, based on its most recent scientific evaluation.

# The REL for Cr(VI) Compounds
NIOSH recommends that airborne exposure to all Cr(VI) compounds be limited to a con centration of 0.2 ^g C r(V I)/m 3 for an 8-hr TWA exposure during a 40-hr workweek. The use of NIOSH M ethod 7605 (or validated equivalents) is recommended for Cr(VI) de term ination. The REL represents the upper limit of exposure for each worker during each work shift. Because of the residual risk of lung cancer at the REL, NIOSH further recom mends that all reasonable efforts be made to reduce exposures to Cr(VI) compounds below the REL. The available scientific evidence sup ports the inclusion of all Cr(VI) compounds into this recommendation. The REL is intended to reduce workers' risk of lung cancer associ ated with occupational exposure to Cr(VI) compounds over a 45-year working lifetime.
Although the quantitative analysis is based on lung cancer mortality data, it is expected that reducing airborne workplace exposures will also reduce the nonmalignant respiratory ef fects of Cr(VI) compounds, which include ir ritated, ulcerated, or perforated nasal septa.
Workers are exposed to various Cr(VI) com pounds in many different industries and work places. Currently there are inadequate exposure assessment and health effects data to quantita tively assess the occupational risk of exposure to each Cr(VI) compound in every workplace. NIOSH used the quantitative risk assessment of chromate production workers conducted by Park et al.  as the basis for the deriva tion of the revised REL for Cr(VI) compounds. This assessment analyzes the data of Gibb et al. , the most extensive database of work place Cr(VI) exposure measurements available, including smoking data on most workers. These chromate production workers were exposed pri marily to sodium dichromate, a soluble Cr(VI) compound. Although the risk of worker expo sure to insoluble Cr(VI) compounds cannot be quantified, the results of animal studies indi cate that this risk is likely as great, if not greater than, exposure to soluble Cr(VI) compounds . The carcinogenicity of in soluble Cr(VI) compounds has been dem on strated in animal and human studies . Animal studies have demonstrated the carcinogenic potential of soluble and insolu ble Cr(VI) compounds . Recent molecular toxi cology studies provide further support for clas sifying Cr(VI) compounds as occupational car cinogens without providing sufficient data to quantify different RELs for specific compounds . Based on its evaluation of the data currently available, NIOSH recommends that the REL apply to all Cr(VI) compounds.
There are inadequate data to exclude any single Cr(VI) compound from this recommendation.
In addition to limiting airborne concentrations of Cr(VI) compounds, NIOSH recommends that dermal exposure to Cr(VI) be prevented in the workplace to reduce the risk of adverse dermal health effects, including irritation, ul cers, skin sensitization, and allergic contact dermatitis.
Properties, Production, and Potential for Exposure

# Physical and Chemical Properties
Chromium (Cr) is a metallic element that oc curs in several valence states, including Cr-4 and Cr-2 through Cr+6. In nature, chromium ex ists almost exclusively in the trivalent (Cr) and hexavalent (Cr) oxidation states. In industry, the oxidation states most commonly found are Cr(0) (metallic or elemental chro mium), Cr(III), and Cr(VI).
Chemical and physical properties of select Cr(VI) compounds are listed in Table 2-1. The chemical and physical properties of Cr(VI) compounds relevant to workplace sampling and analysis are discussed further in Chapter 3, "Measurement of Exposure."

# Production and Use in the United States
In the marketplace, the most prevalent mate rials that contain chromium are chromite ore, chromium chemicals, ferroalloys, and metal. In 2010, the United States consumed about 2% of world chromite ore production in im port ed materials such as chromite ore, chromium chemicals, chromium ferroalloys, chromium metal, and stainless steel . One U.S. company mined chromite ore and one U.S. chemical firm used imported chromite to produce chromium chemicals. Stainless-and heat-resisting-steel producers were the lead ing consumers of ferrochromium. The United
States is a major world producer of chromium metal, chromium chemicals, and stainless steel . Table 2-2 lists select statistics of chromium use in the United States .
Sodium dichromate is the prim ary chemical from which other Cr(VI) compounds are p ro duced. Currently the United States has only one sodium dichromate production facility.
Although production processes may vary, the following is a general description of Cr(VI) com pound production. The process begins by roasting chromite ore with soda ash and varying amounts of lime at very high tem per atures to form sodium chromate. Impurities are removed through a series of pH adjust ments and filtrations. The sodium chromate is acidified with sulfuric acid to form sodium dichromate. Chromic acid can be produced by reacting concentrated sodium dichromate liquor with sulfuric acid. O ther Cr(VI) com pounds can be produced from sodium dichromate by adjusting the pH and adding other compounds. Solutions of Cr(VI) compounds thus formed can then be crystallized, p u ri fied, packaged, and sold. Cr(VI) compounds commonly m anufactured include sodium dichromate, sodium chromate, potassium dichromate, potassium chromate, am monium dichromate, and Cr(VI) oxide. O ther m ate rials containing Cr(VI) commonly m anufac tured include various paint and prim er pig ments, graphic art supplies, fungicides, and corrosion inhibitors.

# Potential Sources of Occupational Exposure 2.3.1 Airborne Exposure
Workers are potentially exposed to airborne Cr(VI) compounds in three different workplace scenarios: (1) when Cr(VI) com pounds are manufactured from other forms of Cr such as in the production of chromates from chromite ore; (2) when products or substances contain ing Cr(VI) are used to manufacture other prod ucts such as chromate-containing paints; or (3) when products containing other forms of Cr are used in processes and operations that result in the formation of Cr(VI) as a by-product, such as in welding.
Many of the processes and operations with worker exposure to Cr(VI) are those in which products or substances that contain Cr(VI) are used to manufacture other products. Cr(VI) compounds impart critical chemical and phys ical properties such as hardness and corrosion resistance to manufactured products. Chro mate compounds used in the manufacture of paints result in products with superior corro sion resistance. Chromic acid used in electro plating operations results in the deposition of a durable layer of chromium metal onto a basemetal part. Anti-corrosion pigments, paints, and coatings provide durability to materials and products exposed to the weather and other extreme conditions.
Operations and processes in which Cr(VI) is formed as a by-product include those utilizing metals containing metallic chromium, includ ing welding and the therm al cutting of metals; steel mills; and iron and steel foundries. Fer rous metal alloys contain chromium metal in varying compositions, lower concentrations in m ild steel and carbon steel, and higher concentrations in stainless steels and other high-chrom ium alloys. The extremely high temperatures used in these operations and processes result in the oxidation of the metal lic forms of chromium to Cr(VI). In welding operations both the base metal of the parts be ing joined and the consumable metal (weld ing rod or wire) added to create the joint have varying compositions of chromium. During the welding process, both are heated to the melting point, and a fraction of the melted metal vapor izes. Any vaporized m etal that escapes the welding-arc area quickly condenses and oxidizes into welding fume, and an appreciable fraction of the chromium in this fume is in the form of Cr(VI) . The Cr(VI) content of the fume and the resultant potential for Cr(VI) exposures are de pendent on several process factors, most impor tantly the welding process and shield-gas type, and the Cr content of both the consumable mate rial and the base metal .
The bioaccessibility of inhaled Cr(VI) from welding fume may vary depending on the fume-generation source. Characterizations of bioaccessibility and biological indices of Cr(VI) exposure have been reported .

# Dermal Exposure
Dermal exposure to Cr(VI) may occur with any task or process in which there is the p o tential for splashing, spilling, or other skin contact with material that contains Cr(VI

# Dermal Exposure
The construction industry has the greatest number of workers at risk of dermal exposure to Cr(VI) due to working with Portland cement. Exposures can occur from contact with a vari ety of construction materials containing Port land cement, including cement, mortar, stucco, and terrazzo. Examples of construction workers with potential exposure to wet cement include bricklayers, cement masons, concrete finishers, construction craft laborers, hod carriers, plas terers, terrazzo workers, and tile setters .
Workers in many other industries are at risk of dermal exposure if there is any splashing, spill ing, or other skin contact with material con taining Cr(VI). Other industries with reported dermal exposure include chromate production ; electroplating ; and grinding of stain less and acid-proof steel .

# Number of U.S. Workers Potentially Exposed
The National Occupational Hazard Survey, conducted by NIOSH from 1972 through 1974, estimated that 2.5 million workers were poten tially exposed to chromium and its compounds . It was estimated that 175,000  and the manufacture of refractory brick, col ored glass, prefabricated concrete products, and treated wood products. The field surveys represent a series of case studies rather than a statistically representative characterization of U.S. occupational exposures to Cr(VI). A limi tation of this study is that for some operations only one or two samples were collected.
The industrial processes and operations were classified into four categories, using the expo sure and exposure-control information collect ed at each site. Each category was determined based on a qualitative assessment of the relative difficulty of controlling Cr(VI) exposures to the existing REL of 1 ^g/m3. The measured ex posures were compared with the existing REL.
For exposures exceeding the existing REL, the extent to which the REL was exceeded was considered, and a qualitative assessment of the effectiveness of the existing controls was made.
An assessment based on professional judgment determined the relative difficulty of improving control effectiveness to achieve the REL. The four categories into which the processes or op erations were categorized are as follows:
1. Those with minimal worker exposures to Cr(VI) in air (Table 2-4).
2. Those with workers' exposures to Cr(VI) in air easier to control to existing NIOSH REL than categories ( 3) and ( 4) (Table 2-5).
3. Those with workers' exposures to Cr(VI) in air moderately difficult to control to the ex isting NIOSH REL (Table 2-6).
4. Those with workers' exposures to Cr(VI) in air most difficult to control to the existing NIOSH REL (Table 2- 7).
The results of the field surveys are summarized in Tables 2-4 through 2-7. The results char acterize the potential exposures as affected by engineering controls and other environmental factors, but not by the use or disuse of PPE. The PBZ air samples were collected outside any re spiratory protection or other PPE (such as welding helmets) worn by the workers. A wide variety of processes and operations were clas sified as those with minimal worker exposures to Cr(VI) in air (Table 2- 4) or where workers' Cr(VI) exposures were determined to be easier to control to the existing REL (Table 2 -5). Most of the processes and operations where control ling workers' Cr(VI) exposures to the existing REL were determined to be moderately dif ficult to control involved joining and cutting metals, when the chromium content of the m a terials involved was relatively high (Table 2-6).
In the category where it was determined to be most difficult to control workers' airborne Cr(VI) exposures to the existing REL, all of the processes and operations involved the ap plication of coatings and finishes (Table 2-    Source: Blade et al. . 'Abbreviations: GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg=manufacturing; MIG = metal inert gas; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification; TIG = tungsten inert gas.
f Concentration value preceded by a "less-than" symbol (<) indicates that the Cr(VI) level in the sampled air was less than the m inim um detectable concentration (i.e., the mass of Cr  collected in the sample was less than the analytical limit of detection ). A concentration value preceded by an "approximately" symbol (~) indicates that Cr(VI) was detectable in the sampled air, but at a level less than the m inim um quantifiable concentration (i.e., the mass of Cr  collected in the sample was between the analytical LOD and limit of quantification ). These concentration values are less precise than fully quantifiable values. *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html.  Properties, Production, and Potential for Exposure  Source: Blade et al. . - Abbreviations: FCAW = flux cored arc welding; GM = geometric mean; GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg = m an ufacturing; MIG = m etal inert gas; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification; SMAW = shield-m etal arc welding; TIG = tungsten inert gas. C oncentration value preceded by a "less-than" symbol (<) indicates that the Cr(VI) level in the sam pled air was less than the m inim um detectable concentration (i.e., the mass of Cr collected in the sample was less than the analytical limit of detection ). *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html.   Source: Blade et al. . - Abbreviations: GM = geometric mean; GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg = m anufacturing; MIG = metal inert gas; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification; TIG = tungsten inert gas.
f Concentration value preceded by a "less-than" symbol (<) indicates that the Cr(VI) level in the sampled air was less than the m inim um detectable concentration (i.e., the mass of Cr collected in the sample was less than the analytical limit of detection ). For some other samples in these sets, Cr(VI) was detectable in the sampled air but at a level less than the m inim um quantifiable concentration (i.e., the mass o f Cr collected in the sample was between the analytical LOD and limit of quantification ). These concentration values are less precise than fully quantifiable values. *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html.   Source: Blade et al. . - Abbreviations: GM = geometric mean; GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg = m anufacturing; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification.
f Concentration value preceded by a "less-than" symbol () indicates that the reported value is an estimate, and the "true" concentration likely is greater, because of air-sampling pum p failure before the end of the intended sampling period. *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html.
 Properties, Production, and Potential for Exposure

# Welding and Thermal Cutting of Metals
Welders are the largest group of workers poten tially exposed to Cr(VI) compounds. Cr(VI)
exposures to welders are dependent on several process factors, most importantly the welding process and shield-gas type, and the Cr content of both the consumable material and the base metal [Keane et al. 2009;Heung et al. 2007;EPRI 2009;Meeker et al. 2010

# Occupational Exposure Limits
The NIOSH REL for all Cr(VI) compounds is 0.

# IDLH Value
An immediately dangerous to life or health (IDLH) condition is one that poses a threat of exposure to airborne contaminants when that exposure is likely to cause death or immediate or delayed perm anent adverse health effects or prevent escape from such an environment . The purpose of establishing an IDLH value is (1) to ensure that the worker can escape from a given contaminated environ ment in the event of failure of the respiratory protection equipment and ( 2) is considered a maximum level above which only a highly reli able breathing apparatus providing maximum worker protection is perm itted .
The IDLH for chromic acid and chromates is 15 mg Cr(VI)/m 3 .

# Future Trends
Industry sectors with the greatest number of workers exposed to Cr(VI) compounds, and the largest number of workers exposed to Cr(VI) compounds above the revised REL, include welding, painting, electroplating, steel mills, and iron and steel foundries . Re cent national and international regulations on workplace and environmental Cr(VI) exposures have stimulated the research and development  of substitutes for Cr(VI). Some defense-related industries are eliminating or limiting Cr(VI) use where proven substitutes are available . However, it is ex pected that worker exposure to Cr(VI) com pounds will continue in many operations u n til acceptable substitutes have been developed and adopted. It is expected that some existing exposures, such as Cr(VI) exposure during the removal of lead chromate paints, will continue to be a risk of Cr(VI) exposure to workers for many years .
Some industries, such as woodworking, print ing ink manufacturing, and printing have de creased their use of Cr(VI) compounds . However, many of these workplaces have only a small num ber of employees or low exposure levels.

# Measurement of Exposure

# Air-Sampling Methods

# Air Sample Collection
There are several m ethods developed by NIOSH and others to quantify Cr(VI) levels in workplace air. Specific air-sampling proce dures such as sampling airflow rates and rec ommended sample-air volumes are specified in each of the methods, but they share similar sample-collection principles. All are suitable for the collection of long-term, time-integrated samples to characterize time-weighted aver age (TWA), personal breathing zone (PBZ) exposures across full work shifts.
Each PBZ sample is collected using a batterypowered air-sampling pum p to draw air at a m easured rate through a plastic cassette containing a filter selected in accordance with the specific sampling m ethod and the consid erations described above. The airflow rate of each air-sampling pump should be calibrated before and after each work shift it is used, and the flow rate adjusted as needed according to the nominal rate specified in the method. Usu ally when measuring a PBZ exposure, the air inlet of the filter cassette is held in the worker's breathing zone by clipping the cassette to the worker's shirt collar, and the pump is clipped to the worker's belt, with flexible plastic tubing connecting the filter cassette and pump. The air inlet should be located so that the exposure is measured outside a respirator or any other personal protective equipment (PPE) being worn by the worker.
W hen sampling for welding fumes, the filter cassette should be placed inside the welding helmet to obtain an accurate measurement of the worker's exposure . The practice of placing the sampling device inside PPE applies only to PPE that is not intended to provide respiratory protection, such as welding helmets or face shields. If the PPE has supplied air, such as a welding hood or an abrasive blasting hood, then the sample is taken outside the PPE .
For the collection of an area air sample, an en tire sampling apparatus (pump, tubing, filter cassette) can be placed in a stationary loca tion. This m ethod can also be used to collect short-term task samples (e.g., 15 m inutes), if high enough concentrations are expected, so that the much smaller air volume collected during the short sample duration contains enough Cr(VI) to exceed the detection limits.
The procedures specified in each m ethod for handling the samples and preparing them for on-site analysis or shipment to an analytical labo ratory should be carefully followed, including providing the proper numbers of field-blank and media-blank samples specified in the method.

# Air Sampling Considerations
Important sampling considerations when deter mining Cr(VI) levels in workplace air have been reviewed  .
It is important to select a filter material that does not react with Cr(VI

# Biological Markers

# Biological Markers of Exposure

# Measurement of chromium in urine
Urinary chromium levels are a measure of to tal chromium exposure as Cr(VI) is reduced within the body to Cr(III). ACGIH  has recommended Biological Exposure Index es (BEIs) for the increase in urinary chromium concentration of 10 ^g/g creatinine during a work shift and 30 ^g/g creatinine at the end of shift at the end of the workweek. These BEIs are applicable to manual metal arc (MMA) stainless steel welding and apply only to work ers with a history of chronic Cr(VI) exposure. Gylseth et al.  Chen et al.  reported an association of skin disease and/or smoking habit with elevat ed urinary Cr levels in cement workers. Smok ing increased urinary Cr levels an average of 25 ^g/L; hand eczema increased urinary Cr levels more than 30 ^g/L. Workers with skin disease who were also smokers had higher u ri nary Cr levels than those with only skin disease or smoking habits. Workers who did not regu larly wear PPE had higher average urinary Cr levels, with the difference between glove users and non-users being the greatest (P < 0.001).
Individual differences in the ability to reduce Cr(VI) have been demonstrated . Individuals with a weaker ca pacity to reduce Cr(VI) have lower urine Cr levels compared with individuals who have a stronger capacity to reduce Cr(VI). Therefore, analyzing only urinary Cr levels may not pro vide an accurate analysis of occupational expo sure and health hazard. Angerer et al.  measured Cr concentra tions in the erythrocytes, plasma, and urine of 103 MM A and/or MIG welders. Personal air monitoring was also conducted. Airborne chromium trioxide concentrations for MMA welders ranged from < 1 to 50 ^g/m3, with 50% < 4 ^g/m 3. Airborne chromium trioxide con centrations for MIG welders ranged from < 1 to 80 ^g/m3 with a median of 10 ^g/m 3. More than half (54%) of measured erythrocyte Cr levels were below the limit of detection (LOD) of 0.6 (J.g/l. Erythrocyte Cr concentration was recommended for its specificity but limited by its low sensitivity. Chromium was detected in the plasma of all welders, ranging from 2.2 to 68.5 (J.g/l; approximately 2 to 50 times higher than the level in non-exposed people. Plasma Cr concentration was recommended as a sen sitive parameter, limited by its lack of specific ity. Erythrocyte, plasma, and urine chromium levels were highly correlated with each other (P < 0.0001).

# Measurement of chromium in blood, plasma, and blood cells

# Biological Markers of Effect

# Renal biomarkers
The concentration levels of certain proteins and enzymes in the urine of workers may indicate early effects of Cr(VI) exposure. Liu et al.  measured urinary N-acetyl-fi-glucosaminidase (NAG), fi2-microglobulin (fi2M), total protein, and microalbumin levels in 34 hard-chrome plat ing workers, 98 nickel-chrome electroplating workers, and 46 aluminum anode-oxidation workers who had no metal exposure and served as the reference group. Hard-chrome platers were exposed to the highest airborne chromi um concentrations (geometric mean 4.20 |ig C r/m 3 TWA) and had the highest urinary NAG concentrations (geometric mean of 4.9 IU/g creatinine). NAG levels were significantly higher among hard-chrome plating workers, while the other biological markers measured were not. NAG levels were significantly associ ated with age (P < 0.05) and gender (P < 0.01) and not associated with employment duration.

# Genotoxic biomarkers
Genotoxic biomarkers may indicate exposure to mutagenic carcinogens. More information about the genotoxic effects of Cr(VI) com pounds is presented in Chapter 5, Section 5.2. Gao et al.  detected DNA strand breaks in human lymphocytes in vitro 3 hours after so dium dichromate incubation, and in male Wistar rat lymphocytes 24 hours after intratracheal instillation. The DNA damage resulting from Cr(VI) exposure is dependent on the reactive intermediates generated . Gao et al.  investigated DNA damage in the lymphocytes of workers exposed to Cr(VI). No significant increases in DNA strand breaks or 8-OHdG levels were found in the lympho cytes of exposed workers in comparison with the lyphocytes of controls. The exposure level for the exposed group was reported to be ap proximately 0.01 mg Cr(VI)/m3. Gambelunghe et al.  evaluated DNA strand breaks and apoptosis in the peripheral lymphocytes of chrome-plating workers. Pre vious air monitoring at this plant indicated total chromium levels from 0.4 to 4.5 |ig/m3. Workers exposed to Cr(VI) had higher levels of chromium in their urine, erythrocytes, and lymphocytes than unexposed controls. The comet assay demonstrated an increase in DNA strand breaks in workers exposed to Cr(VI). The percentage of apoptotic nuclei did not differ between exposed workers and controls. Urinary chromium concentrations correlated with erythrocyte chromium concentrations while lymphocyte chromium concentrations correlated with comet tail moment, an indicator of DNA damage. Kuo et al.  reported positive correlations between urinary 8-OHdG concentrations and both urinary Cr concentration (P < 0.01) and airborne Cr concentration (P < 0.1) in a study of 50 electroplating workers. Li et al.  reported that sperm count and sperm motility were significantly lower (P < 0.05) in the semen of workers exposed to Cr(VI) in comparison with the semen of unexposed control workers. The seminal vol ume and liquefaction time of the semen from the two groups was not significantly different. Workers exposed to Cr(VI) had significantly (P < 0.05) increased serum follicle stimulating hormone levels compared with controls; LH and Cr levels were not significantly different between groups. The seminal fluid of exposed workers contained significantly (P < 0.05) lower levels of lactate dehydrogenase (LDH), lactate dehydrogenase C4 isoenzyme (LDH-x), and zinc; Cr levels were not different.

# Other biomarkers of effect

# Human Health Effects
Most of the health effects associated with oc cupational hexavalent chromium (Cr) ex posure are well known and have been widely reviewed (see Section 4.1.1,Lung Cancer). The following discussion focuses on quantitative exposure-response studies of those effects and new information not previously reviewed by NIOSH . Comprehensive reviews of welding studies are available from ATSDR ; IARC ;and OSHA . Analyses of epidemiologic stud ies with the most robust data for quantitative risk assessment are described in Chapter 6, "Assessment of Risk."

# Cancer

# Lung Cancer
Hexavalent chromium is a well-established oc cupational carcinogen associated with lung cancer and nasal and sinus cancer. In 1989, the International Agency for Research on Cancer (IARC) critically evaluated the published epi demiologic studies of chromium compounds including Cr(VI) and concluded that "there is sufficient evidence in humans for the car cinogenicity of chromium  compounds as encountered in the chromate production, chro mate pigment production and chromium plat ing industries" (i.e., IARC category "Group 1" carcinogen) . The IARC-reviewed studies of workers in those industries and the ferrochromium industry are presented in Tables 4-1  Additional details and reviews of those stud ies are available in the IARC monograph and elsewhere . Although these studies es tablished an association between occupational exposure to chromium and lung cancer, the specific form of chromium responsible for the excess risk of cancer was usually not identified, nor were the effects of tobacco smoking always taken into account. However, the observed excesses of respiratory cancer (i.e., 2-fold to more than 50-fold in chromium production workers) were likely too high to be solely due to smoking. A retrospective cohort study of 398 current and former workers employed for at least 1 year from 1971 through 1989 was conducted in a large chromate production facility in Cas tle Hayne, North Carolina. The plant opened in 1971 and was designed to reduce the high level of chromium exposure found at the com pany's former production facilities in Ohio and New Jersey. The study was performed to determine if there was early evidence for an increased risk of cancer incidence or m ortal ity and to determine whether any increase was related to the level or duration of exposure to Cr(VI). More than 5,000 personal breathing zone (PBZ) samples collected from 1974 through 1989 were available from company records for 352 of the 398 employees. Concentrations of Cr(VI) ranged from below the limit of detec tion (LOD) to 289 ^g/m 3 , with > 99% of the samples less than 50 ^g/m3. Area samples were used to estimate personal m oni toring concentrations for 1971-1972. (Further description of the exposure data is available in Pastides et al. .) Forty-two of the 45 workers with previous occupational exposure to chromium had transferred from the older Painesville, Ohio plant to Castle Hayne. Es timated airborne chromium concentrations at the Ohio plant ranged from 0.05 m g/m 3 to 1.45 m g/m 3 of total chromium for produc tion workers to a maximum of 5.67 m g/m 3 for maintenance workers (mean not reported).

# Epidemiologic exposureresponse analyses of lung cancer
Mortality of the 311 white male Castle Hayne workers from all causes of death (n = 16), cancer (all sites) (n = 6), or lung cancer (n = 2) did not differ significantly from the mortality experience of eight surrounding North Caro lina counties or the United States white male population. Internal comparisons were used to address an apparent "healthy worker" effect in the cohort. Workers with "high" cumula tive Cr(VI) exposure (i.e., > 10 "^g-years" of Cr) were compared with workers who had "low" exposure (i.e., < 10 "^g-years" Cr). No significant differences in cancer risk were found between the two groups after consider ing the effects of age, previous chromium expo sure, and smoking. There was a significantly in creased risk of mortality and cancer, including lung cancer, among a subgroup of employees (11% of the cohort) that transferred from older facilities (odds ratio  for mortality = 1.27 for each 3 years of previous exposure; 90% CI = 1.07-1.51; OR for cancer = 1.22 for each 3 years of previous exposure; 90% CI = 1.03 1.45, controlling for age, years of previous ex posure, and smoking status and including m a lignances among living and deceased subjects).
(The authors reported 90% confidence inter vals, rather than 95%. Regression analyses that excluded transferred employees were not re ported.) The results of this study are limited by a small num ber of deaths and cases and a short follow-up period, and the authors stated "only a large and early-acting cancer risk would have been identifiable" . The average total years between first employment in any chromate production facility and death was 15.2 years; the maximum was 35.3 years .
4.1.1.1.2 U.S. chromate production workers, Maryland ; Gibb et al. ) Gibb et al.  conducted a retrospective analysis of lung cancer mortality in a cohort of Maryland chromate production workers first studied by . The cohort studied by  consisted of 2,101 male salaried and hourly workers (restricted to 1,803 hourly workers) employed for at least 90 days between January 1, 1945, and December 31, 1974, who had worked in new and/or old pro duction sites (Table 4-1). Gibb et al.  identified a study cohort of 2,357 male workers first employed between 1950 and 1974. Work ers who started employment before August 1, 1950, were excluded because a new plant was completed on that date and extensive exposure information began to be collected. Workers starting after that date, but with short-term employment (i.e., < 90 days) were included in the study group to increase the size of the low exposure group. The  study identified deaths through July 1977. Gibb et al.  extended the follow-up period until the end of 1992, and included a detailed ret rospective assessment of Cr(VI) exposure and information about most workers' smoking habits (see Chapter 6, "Assessment of Risk," for further description of the exposure and smok ing data.) The mean length of employment was 3.3 years for white workers (n = 1,205), 3.7 years for nonwhite workers (n = 848), 0.6 years for workers of unknown race (n = 304), and 3.1 years for the total cohort (n = 2,357). The mean follow-up time ranged from 26 years to 32 years; there were 70,736 person-years of observation. The mean cumulative exposures to Cr(VI) were 0.18 m g/m 3-years for nonwhite employees (n = 848) and 0.13 m g/m 3-years for white employees (n = 1,205). The mean expo sure concentration was 43 ^g/m3 .
Lung cancer mortality ratios increased with in creasing cumulative exposure (i.e., mg CrO3/ m 3-years)-from 0.96 in the lowest quartile to 1.57 (95% CI 1.07-2.20; 5-year exposure lag) and 2.24 (95% CI 1.60-3.03; 5-year exposure lag) in the two highest quartiles. The num ber of expected lung cancer deaths was based on age-, race-, and calendar year-specific rates for Maryland. Proportional hazards models that controlled for the effects of smoking predict ed increasing lung cancer risk with increasing Cr(VI) cumulative exposure (relative risks: 1.83 for second exposure quartile, 2.48 for third exposure quartile, and 3.32 for fourth exposure quartile, compared with first quartile of cumulative exposure; confidence intervals not reported; 5-year exposure lag) . For further exploration of time and ex posure variables and lung cancer mortality see Gibb et al. .
In an analysis by industry consultants of simu lated cohort data, lung cancer mortality ratios remained statistically significant for white workers and the total cohort regardless of whether city, county, or state reference popu lations were used . The simu lated data were based on descriptive statistics for the entire cohort provided in Gibb et al. , mainly Table 2.
4.1.1.1.3 U.S. chromate production workers, Ohio )  conducted a retrospec tive cohort study of lung cancer mortality in 482 chromate production workers (four fe male workers) employed > 1 year from 1940 through 1972 in a Painesville, Ohio plant studied earlier by Mancuso ; Proctor et al.  stated that 17 workers who transferred to the North Carolina plant had their exposure profiles in corporated. Their mortality was followed from 1941 through 1997 and compared with United States and Ohio rates. Nearly half (i.e., 45%) of the cohort worked in exposed jobs for 1 to 4 years; 16% worked in them > 20 years. Followup length averaged 30 years, ranging from 1 to 58 years. However, of the workers who died from lung cancer (n = 51), 43% worked 20 or more years and 82% began plant employment before 1955. Their follow-up length averaged 31.6 years, ranging from 7 to 52 years and to taling 14,048 person-years. More than 800 area samples of airborne Cr(VI) from 21 industrial hygiene surveys were available for formation of a job-exposure matrix. The surveys were conducted in 1943, 1945, 1948, and every year from 1955 through 1971. Samples were collect ed in impingers and analyzed colorimetrically for Cr(VI). Concentrations tended to decrease over time. The average airborne concentra tion of Cr(VI) in the indoor operating areas of the plant in the 1940s was 0.72 mg/m3, 0.27 mg/ m 3 from 1957 through 1964, and 0.039 mg/ m 3 from 1965 through 1972 . Further details about the exposure data are in Proctor et al. . For the lung can cer deaths, mean cumulative Cr(VI) exposure was 1.58 m g/m 3-years (range: 0.003-23 mg/ m 3-years) for the cohort and 3.28 m g/m 3-years (range: 0.06-23 m g/m 3-years). The effects of smoking could not be assessed because of in sufficient data.
Cumulative Cr(VI) exposure was divided into five categories to allow for nearly equal num bers of expected deaths from cancer of the trachea, bronchus, or lung in each category: 0.00-0.19, 0.20-0.48, 0.49-1.04, 1.05-2.69, and 2.70-23.0 m g/m 3-years ]. Person-years in each category ranged from 2,369 to 3,220, and the number of deaths from trachea, bronchus, or lung cancer ranged from 3 in the lowest exposure category to 20 in the highest (n = 51). The standardized m or tality ratios (SMRs) were statistically signifi cant in the two highest cumulative exposure categories ] and 4.63 , respectively). SMRs were also significantly increased for year of hire before 1960, > 20 years of employment, and > 20 years since first exposure. The tests for trend across increasing categories of cumulative Cr(VI) ex posure, year of hire, and duration of employ ment were statistically significant (P < 0.005).
A test for departure of the data from linearity was not statistically significant (x2 goodness of fit of linear model; P = 0.23). Van Wijngaarden et al.  reported further examination and discussion of cumulative Cr(VI) exposure and lung cancer mortality in this study and Gibb et al. . Luippold et al.  conducted a retrospec tive cohort mortality study of 617 male and fe male chromate production workers employed at least 1 year at one of two U.S. plants: 430 workers from the North Carolina plant studied by Pastides et al.  (i.e., "Plant 1") and 187 workers hired after the 1980 implementa tion of exposure-reducing process changes at "Plant 2". The study's prim ary goal was to inves tigate possible cancer mortality risks associat ed with Cr(VI) exposure after production p ro cess changes and enhanced industrial hygiene controls (i.e., the "postchange environment"). Employees who had worked less than 1 year in a postchange plant or in a facility using a highlime process were excluded from the cohort. Personal air-monitoring measurements avail able from 1974 to 1988 for Plant 1 and from 1981 through 1998 for Plant 2 indicated that, for most years, overall geometric mean Cr(VI) concentrations for both plants were less than 1.5 ^g/m 3 and area-specific average personal air-sampling values were generally less than 10 ^g/m 3.
Cohort mortality was followed through 1998. The mean time since first exposure was 20.1 years for Plant 1 workers and 10.1 years for Plant 2. Only 27 cohort members (4%) were deceased, and stratified analyses with individ ual exposure estimates and available smoking history data could not be conducted because of the small num ber of deaths. Mortality from all causes was lower than the expected num ber of deaths based on state-specific referent rates, suggesting a strong healthy worker effect (SMR 0.59; 95% CI 0.39-0.85; 27 deaths). Lung cancer mortality was also lower than expected compared with state reference rates (SMR 0.84; 95% CI 0.17-2.44; 3 deaths). However, the study results are limited by a small number of deaths and short follow-up period. The authors stated that the "absence of an elevated lung cancer risk may be a favorable reflection of the postchange environment," but longer followup allowing an appropriate latency period for the entire cohort is needed to confirm this pre liminary conclusion .
4.1.1.1.5 Chromate production workers, Germany (Birk et al. ) Birk et al.  conducted a retrospective co hort study of lung cancer mortality using Cr levels in urine as a biomarker of occupational exposure to Cr(VI). Cohort members were males employed in two German chromate pro duction plants after each plant converted to a no-lime production process, a process believed to result in dusts containing less Cr(VI) . The average duration of Cr(VI) exposure was 9-11 years and mean time since first exposure was 16-19 years, depending on the plant (i.e., Plant A or Plant B). Smoking status from medical examinations/medical re cords was available for > 90% of the cohort as were > 12,000 urinary chromium results col lected during routine employee medical exam inations of workers from both plants.
Mortality was followed through 1998; 130 deaths (22 deaths from cancer of the trachea, bronchus, or lung) were identified among 901 workers employed at least 1 year in the plant with no history of work in a plant before conversion to the no-lime process. The num ber of personyears was 14,684. Although mortality from all causes was significantly less than the expected num ber compared with mortality rates for Germany, the num ber of deaths from cancer of the trachea, bronchus, or lung was greater than expected (SMR = 1.48; 22 deaths observed; 14.83 expected; 95% CI 0.93-2.25). W hen re gional mortality rates were used (i.e., North Rhine-Westphalia), the SMRs were somewhat lower (SMR for all respiratory cancers includ ing trachea, bronchus, and lung = 1.22; 95% CI 0.76-1.85).
Geometric mean values of Cr in urine varied by work location, plant, and time period, and tended to decrease over the years of plant op eration (both plants are now closed). Results of statistical analysis found lung cancer mortality SMRs > 2.00 in the highest cum ulative C r in-urine exposure category, for no exposure lag, 10-year lag, and 20-year lag (e.g., a statisti cally significant highest SMR was reported in the highest exposure category of > 200 ^g/Lyears Cr in urine: SMR 2.09; 12 lung cancer deaths observed; 95% CI 1.08-3.65; regional rates; no exposure lag). However, few study subjects accrued high cumulative exposures of 20 years or more before the end of the study. Cumulative urinary Cr concentrations of > 200 ^g/L-years compared with concentrations < 200 ^g/L-years were associated with a significantly increased risk of lung cancer mortality (OR = 6.9; 95% CI 2.6-18.2), and the risk was unchanged after controlling for smoking .
The use of urinary Cr measurements as a marker for Cr(VI) exposure has limitations, primarily that it may reflect exposure to Cr(VI), Cr(III), or both. In addition, urinary Cr levels may re flect beer consumption or smoking; however, the study authors stated that ". . . workplace ex posures to hexavalent chromium are expected to have a much greater impact on overall uri nary chromium levels than normal variability across individuals due to dietary and metabol ic differences" . were significantly higher. Lung cancer SMRs tended to increase with years since first expo sure for stainless steel welders and mild steel welders; the trend was statistically significant for the stainless steel welders (P  0.5 mg-years/m3) were not significantly higher than SMRs for the low cumulative exposure subgroup (i.e., < 0.5 mg-years/m3) .

# IARC classifies welding fumes and gases as
Group 2B carcinogens-limited evidence of carcinogenicity in humans . Dur ing a 2009 review, IARC found sufficient evi dence for ocular melanoma in welders . NIOSH recommends that "exposures to all welding emissions be re duced to the lowest feasible concentrations us ing state-of-the-art engineering controls and work practices" .

# Nasal and Sinus Cancer
Cases or deaths from sinonasal cancers were reported in five IARC-reviewed studies of chromium production workers in the United States, United Kingdom, and Japan, chromate pigment production workers in Norway, and chromium platers in the United Kingdom (see Tables 4-1 through 4-3). IARC concluded that the findings represented a "pattern of excess risk" for these rare cancers  and in 2009 concluded there is limited evidence for human cancers of the nasal cavity and pa ranasal sinuses from exposure to Cr(VI) com pounds .
Subsequent mortality studies of chromium or chromate production workers employed in New Jersey from 1937 through 1971 and in the Unit ed Kingdom from 1950 through 1976 reported significant excesses of deaths from nasal and si nus cancer (proportionate cancer mortality ra tio (PCMR) = 5.18 for white males, P < 0.05, six deaths observed and no deaths observed in black males ; SMR ad justed for social class and area = 1,538, P < 0.05, four deaths observed ). Cr(VI) exposure concentrations were not reported.
However, an earlier survey of three chromate production facilities in the U.K. found that aver age air concentrations of Cr(VI) in various phas es of the process ranged from 0.002 to 0.88 mg/ m 3 .
Four cases of carcinoma of the nasal region were described in male workers with 19 to 32 years of employment in a Japanese chromate factory . No exposure con centrations were reported.
Although increased or statistically significant numbers of cases of nasal or sinonasal cancer have been reported in case-control or inci dence studies of leather workers (e.g., boot and shoe production) or leather tanning workers in Sweden and Italy , a U.S. mortality study did not find an excess number of deaths from cancer of the nasal cavity . The studies did not report quanti tative exposure concentrations of Cr(VI), and a causative agent could not be determined.
Leather tanning workers may be exposed to several other potential occupational carcino gens, including formaldehyde.

# Nonrespiratory Cancers
Statistically significant excesses of cancer of the oral region, liver, esophagus, and all cancer sites combined were reported in a few studies reviewed by IARC (Tables 4-1 through 4-4). IARC  concluded that "for cancers other than of the lung and sinonasal cavity, no con sistent pattern of cancer risk has been shown among workers exposed to chromium com pounds." More recent reviews by other groups also did not find a consistent pattern of nonrespiratory cancer risk in workers exposed to in haled Cr(VI) . IARC  concluded that "there is little evidence that exposure to chro mium (VI) causes stomach or other cancers."

# Cancer Meta-Analyses
Meta-analysis and other systematic literature re view methods are useful tools for summarizing exposure risk estimates from multiple studies. Meta-analyses or summary reviews of epide miologic studies have been conducted to in vestigate cancer risk in chromium-exposed workers. Steenland et al.  reported overall relative risks for specific occupational lung carcino gens, including chromium. Ten epidemiolog ic studies were selected by the authors as the largest and best-designed studies of chromium production workers, chromate pigment pro duction workers, and chromium platers (i.e., Enterline 1974;Alderson et al. 1981;Satoh et al. 1981;Korallus et al. 1982;Frentzel-Beyme 1983;Davies 1984;Sorahan et al. 1987;Hayes et al. 1989;Takahashi and Okubo 1990). The authors stated that statistically significant SMRs for "all cancer" mortality were mainly due to lung cancer (all cancer: 40 studies; 6,011 deaths; SMR = 112; 95% CI 109-115). Many of the studies contributing to the meta-analyses did not address bias from the healthy worker effect, and thus the results are likely underes timates of the cancer mortality risks. Other limitations of these meta-analyses include lack of (1) exposure characterization of populations such as the route of exposure (i.e., airborne versus ingestion) and ( 2) detail of criteria used to exclude studies based on "no or little chrome exposure" or "no usable data."
Paddle  conducted a meta-analysis of four studies of chromate production w ork ers in plants in the United States ; Pastides et al. ), United King dom (i.e., Davies et al. ), and Germany (i.e., Korallus et al. ) that had undergone modifications to reduce chromium exposure. Most of the modifications occurred around 1960. This meta-analysis of lung cancer "post modification" did not find a statistically signifi cant excess of lung cancer (30 deaths observed; 27.2 expected; risk measure and confidence interval not reported). The author surmised that none of the individual studies in the m e ta-analysis or the meta-analysis itself had suf ficient statistical power to detect a lung cancer risk of moderate size because of the need to exclude employees who worked before plant modifications and the need to incorporate a latency period, thus leading to very small ob served and expected numbers. Meta-analyses of gastrointestinal cancer, laryngeal cancer, or any other nonlung cancer were considered in appropriate by the author because of reporting bias and inconsistent descriptions of the can cer sites . Sjogren et al.  authored a brief report of their meta-analysis of five lung cancer studies of Canadian and European welders exposed to stainless steel welding fumes. The meta-analy sis found an estimated relative risk of 1.94 (95% CI 1.28-2.93) and accounted for the effects of smoking and asbestos exposure . (Details of each study's exposure assess ment and concentrations were not included.)

# Summary of Cancer and Cr(VI) Exposure
Occupational exposure to Cr(VI) has long been associated with nasal and sinus cancer and cancers of the lung, trachea, and bronchus.
No consistent pattern of nonrespiratory cancer risk has been identified.
Few studies of Cr(VI) workers had sufficient data to determine the quantitative relationship between cumulative Cr(VI) exposure and lung cancer risk while controlling for the effects of other lung carcinogens, such as tobacco smoke.
One such study found a significant relation ship between cumulative Cr(VI) exposure (measured as CrO3) and lung cancer mortality ; the data were reanalyzed by NIOSH to further investigate the exposureresponse relationship (see Chapter 6, "Assess ment of Risk").
The three meta-analyses and summary reviews of epidemiologic studies with sufficient statis tical power found significantly increased lung cancer risks with chromium exposure.

# Nonmalignant Effects
Cr(VI) exposure is associated with contact der matitis, skin ulcers, irritation and ulceration of the nasal mucosa, and perforation of the na sal septum . Reports of kidney damage, liver damage, pulmonary congestion and edema, epigastric pain, erosion and discol oration of teeth, and perforated ear drums were found in the literature, and NIOSH concluded that "sufficient contact with any chromium(VI) material could cause these effects" . Later studies that provided quantitative Cr(VI) information about the occurrence of those effects is discussed here. (Studies of nonmalignant health effects and total chromium concentrations  are includ ed in reviews by the Criteria Group for Occu pational Standards  and ATSDR .)

# Respiratory Effects
The ATSDR  review found many re ports and studies published from 1939 to 1991 of workers exposed to Cr(VI) compounds for intermediate (i.e., 15-364 days) to chronic durations that noted these respiratory effects: epistaxis, chronic rhinorrhea, nasal itching and soreness, nasal mucosal atrophy, perforations and ulcerations of the nasal septum, bronchi tis, pneumoconiosis, decreased pulmonary function, and pneumonia.
Five recent epidemiologic studies of three co horts analyzed quantitative information about occupational exposures to Cr(VI) and re spiratory effects. The three worksite surveys described below provide information about workplace Cr(VI) concentrations and health effects at a particular point in time only and do not include statistical analysis of the quantita tive relationship between specific work expo sures and reported health symptoms; thus they contribute little to evaluation of the exposureresponse association. (Studies and surveys pre viously reviewed by NIOSH  are not included.)

# Work site surveys
A NIOSH HHE of 11 male employees in an Ohio electroplating facility reported that most men had worked in the "hard-chrome" area for the majority of their employment (average duration: 7.  Huvinen et al.  No increased prevalences of respiratory symp toms, lung function deficits, or signs of pneu moconiosis (i.e., small radiographic opacities) were found in a 1993 cross-sectional study of stainless steel production workers . The median personal Cr(VI) con centration measured in the steel smelting shop in 1987 was 0.5 ^g/m 3 (i.e., 0.0005 m g/m 3). A retrospective study of 2,357 males first em ployed from 1950 through 1974 at a chromate production plant included a review of clinic and first aid records for physician findings of nasal irritation, ulceration, perforation; and bleeding, skin irritation and ulceration, der matitis, burns, conjunctivitis, and perforated eardrum . The authors also suggested that the proportional hazards model did not find significant associations with all symptoms because the Cr(VI) concentrations were based on annual averages rather than on shorter, more recent average exposures, which may have been a more relevant choice.

# Summary of respiratory effects studies and surveys
A few workplace surveys measured Cr(VI) air concentrations and conducted medical evalua tions of workers. These short-term surveys did not include comparison groups or exposureresponse analyses. Two surveys found U.S. electroplaters and Korean welders with na sal perforations or other respiratory effects; the lowest mean Cr(VI) concentrations at the worksites were 0.004 m g/m 3 for U.S. electro platers and 0.0012 m g/m 3 for Korean welders .
Cross-sectional epidemiologic studies of chromeplating workers  and stainless steel production workers  found no nasal perforations at average chromic acid concentra tions < 2 ^g/m3. The platers experienced nasal ulcerations and/or septal perforations and tran sient reductions in lung function at mean con centrations ranging from 2 ^g/m3 to 20 ^g/m3. Nasal mucosal ulcerations and/or septal perfo rations occurred in plating workers exposed to peak concentrations of 20-46 ^g/m3.
The best exposure-response information to date is from the only epidemiologic study with sufficient health and exposure data to estimate the risks of ulcerated nasal septum, ulcerated skin, perforated nasal septum, and perforated eardrum over time . This retrospective study reviewed medical records of more than 2,000 male workers and analyzed thousands of airborne Cr(VI) measurements collected from 1950 through 1985. More than 60% of the cohort had experienced an irritated nasal septum (68.1%) or ulcerated nasal sep tum (62.9%) at some time during their employ ment. The median Cr(VI) exposure (measured as CrO3) at the time of first diagnosis of these findings and all others (i.e., perforated nasal septum, bleeding nasal septum, irritated skin, ulcerated skin, dermatitis, burn, conjunctivitis, perforated eardrum) was 0.020 m g/m 3-0.028 m g/m 3 (20 |ig/m3-28 |ig/m3). O f particular concern is the finding of nasal and ear effects occurring in less than 1 month: the median time from date first employed to date of first diagnosis was less than 1 m onth for irritated nasal septum (20 days), ulcerated nasal septum (22 days), and perforated eardrum (10 days). A proportional hazards model predicted relative risks of 1.20 for ulcerated nasal septum, 1.11 for ulcerated skin, and 1.35 for "perforated ear" for each 0.1 m g/m 3 increase in ambient CrO 3.
The authors noted that the chrome platers studied by Lindberg and Hedenstierna  were exposed to chromic acid, which may be more irritative than the chromate chemicals occurring with chromate production .

# Asthma
Occupational asthma caused by chromium ex posure occurs infrequently compared with al lergic contact dermatitis .
The exposure concentration below which no cases of occupational asthma would occur, including cases induced by chromium com pounds, is not known . Furthermore, that concentration is likely to be lower than the concentration that initially led to the employee's sensitization . Case series of asthma have been report ed in U.K. electroplaters , Finnish stainless steel welders , Russian alumina industry workers ; Korean metal plating, construc tion, and cement manufacturing workers, ; and a cross-sectional study of U.K. electroplaters . However, there are no quantitative exposure-response as sessments of asthma related to Cr(VI) in occu pational cohorts, and further research is needed.

# Dermatologic Effects
Cr  .
No occupational studies have examined the quantitative exposure-response relationship be tween Cr(VI) exposure and a specific dermatologic effect, such as ACD; thus, an exposure-response relationship has not been clearly established. O ther assessments evaluated the occurrence of ACD from contact with Cr(VI) in soil (e.g., Proctor et al. ; Paustenbach et al. ; Bagdon and Hazen ; Stern et al. ; Nethercott et al. ).

# Reproductive Effects
The six available studies of pregnancy occur rence, course, or outcome reported little or no information about total Cr or Cr(VI) concen trations at the workplaces of female chromium production workers [Shmitova 1978[Shmitova , 1980 or male welders that were also spouses [Bonde et al. 1992;Hjollund et al. 1995Hjollund et al. , 1998Hjollund et al. , 2000. The lack of consistent findings and exposureresponse analysis precludes formation of con clusions about occupational Cr(VI) exposure and adverse effects on pregnancy and child birth. Further research is needed.

# Other Health Effects

# Mortality studies
More than 30 studies examined numerous non cancer causes of death in jobs with potential chromium exposure, such as chromate produc tion, chromate pigment production, chromium plating, ferrochrom ium production, leather tanning, welding, m etal polishing, cement finishing, stainless steel grinding or produc tion, gas generation utility work, and paint production or spraying. (Studies previously cited by NIOSH [1975NIOSH [ , 1980 are not included.)
Most studies found no statistically significant increases (i.e., P < 0.05) in deaths from nonmalignant respiratory diseases, cardiovascular diseases, circulatory diseases, accidents, or any other noncancer cause of death that was in cluded . However, these studies did not in clude further investigation of the nonsignifi cant outcomes and therefore do not confirm the absence of an association.
Some studies did identify significant increases in deaths from various causes . However, the findings were not consistent: no noncancer cause of death was found to be significantly increased in at least five studies. Furthermore, exposureresponse relationships were not examined for those outcomes. Therefore, the results of these studies do not support a causal association between occupational Cr(VI) exposure and a nonmalignant cause of death. NIOSH  concluded that Cr(VI) ex posure could cause other health effects such as kidney damage, liver damage, pulmonary congestion and edema, epigastric pain, and erosion and discoloration of the teeth. Other effects of exposure to chromic acid and chro mates not discussed elsewhere in this section include eye injury, leukocytosis, leukopenia, and eosinophilia . Acute renal failure and acute chromi um intoxication occurred in a male worker fol lowing a burn with concentrated chromic acid solution to 1% of his body .

# Other health effects
There has been little post-1975 research of those effects in occupational cohorts. Furthermore, there is insufficient evidence to conclude that occupational exposure to respirable Cr(VI) is related to other health effects infrequently reported in the literature after the NIOSH  review. These effects included cerebral arachnoiditis in 47 chromium industry work ers  and cases of gastric disturbances (e.g., chronic gastritis, polyps, ulcers, and mucous membrane ero sion) in chromium salt workers . Neither study analyzed the relation ship of air Cr(VI) concentrations and health effects, and one had no comparison group .   ------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------- Davies [1978Davies [ , 1979Davies [ , 1984  1-9 years' 3 2.0f followed to end of employment 1982.
 10 years' 6 3.2f employment Source: Adapted from IARC . Dash in "Estimated relative risk" indicates not reported. ^Significant at 95% level. fP fo r trend < 0.01.

# Experimental Studies
Experimental studies provide important infor mation about the pharmacokinetics, mecha nisms of toxicity, and potential health effects of hexavalent chromium (Cr) compounds. Studies using cell culture and in vitro tech niques, animal models, and human volunteers provide data about these compounds. The results of these experimental studies, when considered with the results of other health ef fects studies, provide a more comprehensive database for the evaluation of the mechanisms and health effects of occupational exposure to Cr(VI) compounds.

# Pharmacokinetics
The absorption of inhaled Cr(VI) depends on the oxidation state, particle size, and solubility of the compound . Large par ticles (> 10 ^m) of inhaled Cr(VI) compounds are deposited in the upper respiratory tract; smaller particles can reach the lower respira tory tract. Some of the inhaled Cr(VI) is re duced to trivalent chromium (Cr) in the epithelial or interstitial lining fluids within the bronchial tree. The extracellular reduction of Cr(VI) to Cr(III) reduces the cellular uptake of chromium because Cr(III) compounds can not enter cells as readily as Cr(VI) compounds. At physiological pH most Cr(VI) compounds are tetrahedral oxyanions that can cross cell membranes. Cr(III) compounds are predom i nantly octahedral structures to which the cell membrane is practically impermeable. Cr(III) can enter the cell only via pinocytosis . The Cr(VI) ions that cross the cell m em brane become a target of intracellular reductants. The Cr(VI) concentration decreases with increasing distance from the point of entry as Cr(VI) is reduced to Cr(III). The Cr(III) ions are transported to the kidneys and excreted.
Inhaled Cr(VI) that is not absorbed in the lungs may enter the gastrointestinal tract fol lowing mucociliary clearance. Much of this Cr(VI) is rapidly reduced to Cr(III) by reductants in the saliva and gastric juice and excret ed in the feces. The remaining 3% to 10% of the Cr(VI) is absorbed from the intestines into the blood stream, distributed throughout the body, transported to the kidneys, and excreted in the urine .

# Mechanisms of Toxicity
The possible mechanisms of the genotoxicity and carcinogenicity of Cr(VI) compounds have been reviewed . However, the exact mechanisms of Cr(VI) toxicity and carcinogenicity are not yet fully understood. A significant body of research suggests that Cr(VI) carcinogenicity may result from damage mediated by the bio reactive products of Cr(VI) reduction, which include the Cr(VI) intermediates (Cr and Cr), and reactive oxygen species (ROS). Factors that may affect the toxicity of a chro mium compound include its bioavailability, oxidative properties, and solubility .
Intracellular Cr(VI) undergoes metabolic re duction to Cr(III) in microsomes, in m ito chondria, and by cellular reductants such as ascorbic acid, lipoic acid, glutathione, cysteine, reduced nicotinamide adenine dinucleotide phosphate (NADPH), ribose, fructose, arabinose and diol-and thiol-containing molecules, as well as NADPH/flavoenzymes. Although the extracellular reduction of Cr(VI) to Cr(III) is a mechanism of detoxification as it decreases the num ber of bioavailable Cr(VI) ions, intracel lular reduction may be an essential element in the mechanism of intracellular Cr(VI) toxicity.
The intracellular Cr(VI) reduction process generates products including Cr(V), Cr(IV), Cr(III) molecular oxygen radicals, and other free radicals. The molecular oxygen is reduced to superoxide radical, which is further reduced to hydrogen peroxide (H2O2) by superoxide dismutase (SOD). H2O2 2 rea2cts with Cr(V), Cr(IV) or Cr(III) to generate hydroxyl radi cals ( 'OH) via the Fenton-like reaction, and it undergoes reduction-oxidation cycling . The high concentration of oxy gen radicals and other free radical species gen erated in the process of Cr(VI) reduction may result in a variety of lesions on nuclear chro matin, leading to mutation and possible neo plastic transformation .
In the presence of cellular reducing systems that generate chromium intermediates and hydroxyl radicals, Cr(VI) salts induce various types of DNA damage, resulting either from the breakage of existing covalent bonds or the formation of new covalent bonds among molecules, such as DNA interstrand cross links, DNA-protein crosslinking, DNA double strand breaks, and depurination. Such lesions could lead to mutagenesis and ultimately to carcinogenicity . The oxidative damage may result from a direct binding of the reactive Cr(VI) intermediates to the DNA or may be due to the indirect effect of ROS interactions with nuclear chromatin, depending on their intracellular location and proximity to DNA . Cr(VI) does not bind irreversibly to na tive DNA and does not produce DNA lesions in the absence of the microsomal reducing sys tems in vitro .
In addition to their oxidative properties, the solubility of Cr(VI) compounds is another im portant factor in the mechanism of their carci nogenicity. Animal studies indicate that insol uble and sparingly soluble Cr(VI) compounds may be more carcinogenic than soluble chro mium compounds .
Particles of lead chromate, a relatively insoluble Cr(VI) compound, when added directly to the media of mammalian cell culture, induced cell transformation . When injected into whole animals, the particles pro duced tumors at the site of injection . Several hypotheses have been pro posed to explain the effects of insoluble Cr(VI) compounds. One hypothesis proposes that particles dissolve extracellularly, resulting in chronic, localized exposure to ionic chromate. This hypothesis is consistent with studies dem onstrating that extracellular dissolution is re quired for lead chromate-induced clastogenesis . Xie et al.  demonstrated that lead chromate clastogenesis in human bronchial cells is medi ated by the extracellular dissolution of the par ticles but not their internalization.
Another hypothesis suggests that a high Cr(VI) concentration is created locally inside the cell during internalization of Cr(VI) salt particles by phagocytosis .
High intracellular local Cr(VI) concentrations can generate high concentration of ROS inside the cell, which may overwhelm the local ROS scavenging system and result in cytotoxic ity and genotoxicity . Highly soluble compounds do not generate such high local concentrations of Cr(VI). However, once inside the cell, both soluble (sodium chromate) and insoluble (lead chromate) Cr(VI) com pounds induce similar amounts and types of concentration-dependent chromosomal dam age in exposed cultured mammalian cells [Wise et al. 1993[Wise et al. , 2002[Wise et al. , 2003. Pretreatment of these cells with ROS scavengers such as vitamin E or C prevented the toxic effects of both sodium chromate and lead chromate.
Numerous studies report a broad spectrum of cellular responses induced by exposure to vari ous Cr(VI) compounds. These cytotoxic and genotoxic responses are consistent with mech anistic events associated with carcinogenesis. Studies in human lung cells provide data regard ing the genotoxicity of many Cr(VI) compounds . Cr(VI) compounds induce transforma tion of human cells, including bronchial epithe lial cells .
Barium chromate induced concentrationdependent chromosomal damage, including chromatid and chromosomal lesions, in h u m an lung cells after 24 hours of exposure . Lead chromate and soluble sodium chromate induced concentrationdependent chromosomal aberration in h u man bronchial fibroblasts after 24 hours of exposure . Cotreatm ent of cells with vitamin C blocked the chromate induced toxicity. Calcium chro mate induced DNA single-strand breaks and DNA protein cross-links in a dose-dependent m anner in three cell lines. Exposing hum an lung cell cultures to lead chromate induced chrom osom e instability including centrosome amplification and aneuploidy  and spindle assembly checkpoint bypass . Sodium dichromate generated ROS that increased the level and ac tivity of the protein p53 in human lung epithe lial cells. In norm al cells the protein p53 is usu ally inactive. It is usually activated to protect cells from tumorigenic alterations in response to oxidative stress and other stimuli such as ultraviolet or gamma radiation. An increased 'OH concentration activated p53; elimination of 'OH by H2O2 scavengers inhibited p53 acti vation .
The ROS (mainly H2O2) formed during p o tassium chromate reduction induced the ex pression of vascular endothelial growth factor (VEGF) and hypoxia-induced factor 1 (HIF-1) in DU145 hum an prostate carcinom a cells. VEGF is the essential protein for tum or angiogenesis. HIF-1, a transcription factor, regulates the expression of many genes including VEGF. The level of HIF-1 activity in cells correlates with the tumorigenic response and angiogenesis in nude mice, is induced by the expression of various oncogenes, and is overexpressed in many human cancers .
Early stages of apoptosis have been induced in human lung epithelial cells in vitro following exposure to potassium dichromate. Scavengers of ROS, such as catalase, aspirin, and N-acetyl-L-cysteine, decreased apoptosis induced by Cr(VI); reductants such as NADPH and gluta thione enhanced it. Apoptosis can be triggered by oxidative stress. Agents that promote or suppress apoptosis may change the rates of cell division and lead to the neoplastic transform a tion of cells .
The treatment of mouse macrophage cells in vitro with sodium chromate induced a dosedependent activation of the transcription en hancement factors NF-kB and AP-1 .
Sodium dichromate increased tyrosine phos phorylation in hum an epithelial cells. The phosphorylation could be inhibited by anti oxidants . Tyrosine phos phorylation is essential in the regulation of many cellular functions, including cancer de velopment .
Human lung epithelial A549 cells exposed to potassium dichromate in vitro generated ROSinduced cell arrest at the G2/M phase of the cell proliferation cycle at relatively low con centrations and apoptosis at high concentra tions. Interruption of the proliferation process is usually induced in response to cell damage, particularly DNA damage. The cell remains arrested in a specific cell cycle phase until the damage is repaired. If damage is not repaired, mutations and cell death or cancer may result .
Gene expression profiles indicate that expos ing human lung epithelial cells to potassium dichromate in vitro resulted in up regulation of the expression of 150 genes, and down regu lation of 70 genes. The analysis of gene expres sion profiles indicated that exposure to Cr(VI) may be associated with cellular oxidative stress, protein synthesis, cell cycle regulation, and on cogenesis .
These in vitro studies have limitations of m od els of human exposure because they cannot account for the detoxification mechanisms that take place in intact physiological systems.
However, these studies represent a body of data on cellular responses to Cr(VI) that pro vide important information regarding the p o tential genotoxic mechanisms of Cr(VI) com pounds. The cellular damage induced by these compounds is consistent with the mechanisms of carcinogenesis.

# Health Effects in Animals
Chronic inhalation studies provide the best data for extrapolation to airborne occupational exposure. Only a few of these chronic inhala tion studies have been conducted using Cr(VI) compounds. Glaser et al.  conducted chronic inhalation studies of chromic acid mist exposure in mice. Glaser et al.  conducted chronic inhalation studies of sodium dichromate exposure in rats. Stein hoff et al.  conducted an intratracheal study of sodium dichromate exposure in rats. Levy et al.  conducted an intrabronchial implantation study of various Cr(VI) materials in rats. The results of these animal studies sup port the classification of Cr(VI) compounds as occupational carcinogens. Glaser et al.  exposed male Wistar rats to whole body aerosol exposures of sodium di chromate at 0, 25, 50, 100, or 200 |ig Cr(VI)/m3 for 22 hr/day, 7 days/wk for 28 or 90 days. Twenty rats were exposed at each dose level. An addi tional 10 rats were exposed at 50 ^g for 90 days followed by 2 months of nonexposure before sacrifice. The average mass median diameter (MMD) of the aerosol particles was 0.2 ^m. Significant increases (P < 0.05) occurred in the serum triglyceride, phospholipid contents, and e 2 mitogen-stimulated splenic mean T-lymphocyte count of rats exposed at the 200 ^g/m3 level for 90 days. Serum total immunoglobulins were statistically increased (P < 0.01) for the 50 and 100 ^g exposure groups.

# Subchronic Inhalation Studies
To further study the humoral immune effects, half of the rats in each group were immunized with sheep red blood cells 4 days before sac rifice . The prim ary anti body responses for IgM B-lymphocytes were statistically increased (P < 0.05) for the groups exposed to 25 |ig Cr(VI)/m 3 and higher. The mitogen-stimulated T-lymphocyte response of spleen cells to Concanavalin A was significant ly increased (P < 0.05) for the 90-day, 200 |ig/ m 3 group compared with the control group. The mean macrophage cell counts were sig nificantly lower (P < 0.05) than control values for only the 50 and 200 |ig Cr(VI)/m 3, 90-day groups. Alveolar m acrophage phagocytosis was statistically increased in the 50 ^g level of the 28-day study, and the 25 and 50 |ig m g/m 3 Cr(VI) levels of the 90-day study (P < 0.001). A significant depression of phagocytosis oc curred in the 200 ^g/m 3 group of the 90-day study versus controls.
A group of rats exposed to 200 |ig Cr(VI)/m3 for 42 days and controls received an acute iron oxide particulate challenge to study lung clearance rates during a 49-day nonexposure post-challenge period . Iron oxide clearance was dramatically and increas ingly decreased in a bi-exponential m anner for the group exposed to Cr(VI) compared with the controls. Glaser et al.  studied lung toxicity in ani mals exposed to sodium dichromate aerosols. Groups of 30 male Wistar rats were exposed to 0, 50, 100, 200, or 400 |ig Cr(VI)/m 3 for 22 hr/ day, 7 days/week for 30 or 90 days, followed by a 30-day nonexposure recovery period. Aerosol mass median aerodynamic diameter (MMAD) ranged from 0.28 to 0.39 ^m. Sac rifices of 10 rats occurred after experimental days 30, 90, and 120. The only sign or symp tom induced was an obstructive dyspnea pres ent at the 200 and 400 ^g/m3 levels. Statistically significant reductions in body weight gains were present at 30 days for the 200 ^g level, with similar reductions for the 400 |ig level rats at the 30, 90, and 120-day intervals. White blood cell counts were statistically increased (P < 0.05) for all four dichromate exposure groups for the 30-and 90-day intervals, but the white blood cell counts returned to control levels after 30 days of nonexposure. The lung parameters studied had statistically signifi cant dose-related increases after either 30 or 90 days of inhalation exposure to dichromate; some remained elevated despite the nonexpo sure recovery period. A No Observed Adverse Effect Level (NOAEL) was not achieved.
Bronchoalveolar lavage (BAL) provided infor mation about pulmonary irritation induced by sodium dichromate exposure in these rats . Total protein levels present on day 30 progressively decreased at days 90 and 120 but remained above control values. Alveo lar vascular integrity was compromised as BAL albumin levels were increased for all treatment groups, with only the 200 and 400 ^g/m3 levels remaining above those of the controls at the end of the recovery period. Lung cell cytotoxicity as measured by cytosolic lactate dehydrogenase, and lysosomal fi-glucuronidase was increased by dichromate exposure but normalized dur ing the post-exposure period. Mononuclear macrophages comprised 90% of recovered to tal BAL cells. The two highest exposure groups had equal increases throughout the treatment period, but they returned to normal during the recovery period. These macrophages had high er cell division rates, sometimes were multinuclear, and were bigger when compared with control cells. Sodium dichrom ate exposure induced statistically significant increased lung weights for the 100, 200, and 400 ^g/m 3 groups throughout the study, including the nonexpo sure period. Histopathology of lung tissue re vealed an initial bronchoalveolar hyperplasia for all exposure groups at day 30, while only the 200 and 400 ^g/m3 levels retained some lower levels of hyperplasia at study day 120. There was also an initial lung fibrosis observed in some animals at the levels above 50 ^g/m3 on day 30, which was not present during the remainder of the study. Lung histiocytosis re mained elevated throughout the entire study for all treatment groups.

# Chronic Inhalation Studies
Adachi et al.  exposed 50 female ICR/JcI mice to 3.63 mg Cr(VI)/m 3 chromic acid mist (85% of mist measuring < 5 ^m) for 30 m in/ day, 2 days/week for 12 months, followed by a 6-month nonexposure recovery period. Prolif erative changes were observed within the respira tory tract after 26 weeks of chromate exposure. Pin-hole-sized perforations of the nasal septum occurred after 39 weeks at this exposure level. When the incidence rates for histopathological findings (listed below) for chromate-exposed animals were compared for successive study pe riods, the treatment group data were generally similar for weeks 40-61 when compared with weeks 62-78, with the exception of the induction of two adenocarcinomas of the lungs present in two females at the terminal 78-week sacrifice. The total study pathology incidence rates for the 48 chromate-exposed females were the following: perforated nasal septum (n = 6), tracheal (n = 43)/ bronchial (n = 19) epithelial proliferation, and emphysema (n = 11), adenomatous metaplasia (n = 3), adenoma (n = 5), and adenocarcinoma (n = 2) of the lungs. Total control incidence rates for the 20 females examined were confined to the lung: emphysema (n = 1), adenomatous metapla sia (n = 1), and adenoma (n = 2). Adachi  exposed 43 female C57BL mice to 1.81 mg Cr(VI)/m 3 chromic acid mist (with 85% of mist measuring ~5 ^m) for 120 m in/ day, 2 days/week for 12 months, followed by a 6-month nonexposure recovery period. Twen ty-three animals were sacrificed at 12 months, with the following nontumorigenic histologi cal changes observed: nasal cavity perforation (n = 3); tracheal hyperplasia (n = 1); and em physema (n = 9) and adenomatous metaplasia (n = 4) of the lungs. A terminal sacrifice of the 20 remaining females occurred at 18 months, which demonstrated perforated nasal sep ta (n = 3) and papillomas (n = 6); laryngeal/ tracheal hyperplasia (n = 4); and emphysema (n = 11), adenomatous metaplasia (n = 5), and adenoma (n = 1) of the lungs. Only emphyse ma (n = 2) and lung metaplasia (n = 1) were observed in control females sacrificed after week 78.
Glaser et al.  exposed groups of 20 male Wistar rats to aerosols of 25, 50, or 102 ^g/m3 sodium dichromate for 22 to 23 hr/day, 7 days/ week for 18 months, followed by a 12-month nonexposure recovery period. Mass median diameter of the sodium dichromate aerosol was 0.36 ^m. No clinical sign of irritation in duced by Cr(VI) was observed in any treated animal. Statistically increased liver weights (+26%) were observed at 30 months for the 102 ^g/m3 dichromate males. Weak accumu lations of pigment-loaded macrophages were present in the lungs of rats exposed to 25 ^g/m3 sodium dichromate; moderate accumulations were present in rats exposed to 50 and 102 ^g/ m 3 sodium dichromate. Three prim ary lung tu mors occurred in the 102 ^g Cr(VI)/m 3 group: two adenomas and one adenocarcinoma. The authors concluded that the 102 ^g Cr(VI)/m3 level of sodium dichromate induced a weak lung carcinogenic effect in rats exposed under these conditions.

# Intratracheal Studies
Steinhoff et al.  dosed Sprague-Dawley rats via intratracheal instillation with equal to tal weekly doses of sodium dichromate for 30 months: either five consecutive daily doses of 0.01, 0.05, or 0.25 mg/kg or one weekly dose of 0.05, 0.25, or 1.25 mg/kg. Each group consisted of 40 male and 40 female rats. Groups left u n treated or given saline were negative controls. Body weight gains were suppressed in males treated with single instillations of 1.25 mg/ kg of sodium dichromate. Chromate-induced nonneoplastic and neoplastic lesions were de tected only in the lungs. The nonneoplastic pulmonary lesions were primarily found at the maximum tolerated irritant concentration lev el for the high dose sodium dichromate group rather than having been dependent upon the total dose administered. The nonneoplastic pulmonary lesions occurred predominantly in the highest dose group and were character ized by fibrotic regions that contained residual distorted bronchiolar lumen or cellular inflam matory foci containing alveolar macrophages, proliferated epithelium, and chronic inflam matory thickening of the alveolar septa plus at electasis. The neoplastic lesions were non-fatal lung tumors found in these chromate-treated animals. Fourteen rats given single weekly in stillations of 1.25 mg sodium dichromate/kg developed a significant (P < 0.01) number of tumors: 12 benign bronchioalveolar adeno mas and 8 malignant tumors including 2 bronchioalveolar adenocarcinomas and 6 squamous cell carcinomas. Only one additional tumor, a bronchioalveolar adenocarcinoma, was found in a rat that had received single weekly instilla tions of 0.25 mg/kg sodium dichromate.

# Intrabronchial Studies
Levy et al.  conducted a 2-year intra bronchial implantation study of 20 chromiumcontaining materials in Porton-W istar rats.
Test groups consisted of 100 animals with equal numbers of male and female rats. A small, hook-equipped stainless steel wire mesh basket containing 2 mg of cholesterol and test mate rial was inserted into the left bronchus of each animal. Two positive control groups received pellets loaded with 20-methylcholanthrene or calcium chromate. The negative control group received a blank pellet loaded with cholesterol. Pulmonary histopathology was the prim ary parameter studied. There were inflammatory and metaplastic changes present in the lungs and bronchus, with a high level of bronchial irritation induced by the presence of the bas ket alone. A total of 172 tumors were obtained throughout the study, with only 18 found at the terminal sacrifice. Nearly all tumors were large bronchial keratinizing squamous cell carcino mas that affected a major part of the left lung and were the cause of death for most affected animals. The authors noted that no squamous cell carcinomas had been found in 500 of their historical laboratory controls.
In Table 5-1, study data from Levi et al.  were transformed by NIOSH to present the rank order of tum or induction potential for the test compounds through calculation of the mean ^g of Cr(VI) required to induce a single bronchiolar squamous cell carcinoma. The rank order of tum or induction poten tial for the positive Cr(VI) compounds using these data was the following: strontium > cal cium > zinc > lead, chromic acid > sodium di chromate > barium. The role solubility played in tum or production for these test materials was inconsistent and not able to be determined.

# Chronic Oral Studies
The National Toxicology Program (NTP) con ducted 2-year drinking water studies of sodium dichromate dehydrate (SDD) in rodents . Male and female F344/N id en tified also as being a lead chrom ate containing group. No lung tum ors were previously found in 500 negative historical control rats that h ad basket implants. f21 squam ous cell carcinomas and one anaplastic carcinoma o f the lung.
rats and female B6C3F1 mice were exposed to 0, 14.3, 57.3, 172, or 516 mg/L SDD, and male mice to 0, 14.3, 28.6, 85.7, or 257.4 mg/L SDD. Statistically significant concentration-related increased incidences of neoplasms of the oral cavity in male and female rats, and of the small intestine in male and female mice, were report ed. The NTP concluded that these results pro vide clear evidence of the carcinogenic activ ity of SDD in rats and mice . This conclusion was reinforced by the similar results reported between the sexes in both rats and mice.

# Reproductive Studies
Reviews and analyses of the animal studies of the reproductive effects of Cr . Negative stud ies have also been reported; potassium dichromate administered in the diet to mice and rats did not result in adverse reproductive effects or outcomes in rats or mice [NTP 1996a,b;. Inhalation studies in male and female rats did not result in adverse reproductive effects [Gla ser et al. 1985[Gla ser et al. , 1986[Gla ser et al. , 1988

# Dermal Studies
Dermal exposure is another important route of exposure to Cr(VI) compounds in the work place. Experimental studies have been conduct ed using human volunteers, animal models, and in vitro systems to investigate the dermal effects of Cr(VI) compounds.

# Human Dermal Studies
Mali et al.  reported the permeation of intact epidermis by potassium dichromate in human volunteers in vivo. Sensitization was re ported in humans exposed to this Cr(VI) com pound but not Cr(III) sulfate. Baranowska-Dutkiewicz  conducted 27 Cr(VI) absorption experim ents on seven hum an volunteers. The forearm skin absorp tion rate for 0.01 molar solution of sodium chromate was 1.1 |ig/cm2/hr, for 0.1 molar so lution it was 6.5 |ig/cm2/hr, and for 0.2 molar solution it was 10.0 |ig/cm2/hr. The amount of Cr(VI) absorbed as a percent of the applied dose decreased with increasing concentration.
The absorption rate increased as the Cr(VI) concentration applied increased, and it de creased as the exposure time increased.
Corbett et al.  immersed four human volunteers below the shoulders in water con taining 22 mg/L potassium dichromate for 3 hours to assess their uptake and elimination of chromium. The concentration of Cr in the urine was used as the measure of systemic up take. The total Cr excretion above historical background ranged from 1.4 to 17.5 |ig. The dermal uptake rates ranged from approximate ly 3.3 x 10-5 to 4.1 x 10-4 ^g/cm2/hr, with an average of 1.5 x 10-4. One subject had a dermal uptake rate approximately seven times higher than the average for the other three subjects.

# Animal Dermal Studies
Mali et al.  demonstrated the experi mental sensitization of 13 of 15 guinea pigs by injecting them with 0.5 mg potassium dichromate in Freund adjuvant subdermally twice at 1-week intervals.
Gad et al.  conducted standard dermal LD50 tests to evaluate the acute toxicity of sodi um chromate, sodium dichromate, potassium dichromate, and ammonium dichromate salts in New Zealand white rabbits. All salts were tested at 1.0, 1.5, and 2.0 g/kg dosage, with the exception of sodium chromate, which was test ed at the two higher doses only. In males, the dermal LD50 ranged from a mean of 0.96 g/kg (SD = 0.19) for sodium dichromate to 1.86 g/ kg (SD = 0.35) for ammonium dichromate. In females the dermal LD50 ranged from a mean of 1.03 g/kg (SD = 0.15) for sodium dichromate to 1.73 g/kg (SD = 0.28) for sodium chromate. Each of the four salts, when moistened with saline and occluded to the skin for 4 hours, caused marked irritation. Occlusion of each salt on the skin of the rabbit's back for 24 hours caused irreversible cutaneous damage. Liu et al.  demonstrated the reduction of an aqueous solution of sodium dichromate to Cr(V) on the skin of Wistar rats using in vivo electron paramagnetic resonance spectroscopy.
Removal of the stratum corneum by stripping the skin with surgical tape 10 times before the application of the dichromate solution increased the rates of formation and decay of Cr(V).

# In Vitro Dermal Studies
Gammelgaard et al.  conducted chro mium permeation studies on full thickness hu man skin in an in vitro diffusion cell system. Application of 0.034 M potassium chromate to the skin resulted in significantly higher levels of chromium in the epidermis and dermis, com pared with Cr(III) nitrate and Cr(III) chloride. Chromium levels in the epidermis and dermis increased with the application of increasing concentrations of potassium chromate up to 0.034 M Cr. Chromium skin levels increased with the application of potassium chromate solutions with increasing pH. The percentage of Cr(VI) converted to Cr(III) in the skin was largest at low total chromium concentrations and decreased with increasing total concentra tions, indicating a limited ability of the skin to reduce Cr(VI).
Van Lierde et al.  conducted chromium permeation studies on human and porcine skin using a Franz static diffusion cell. Potassium dichromate was determined to permeate hu man and pig skin after 168 hours of exposure, while the Cr(III) compounds tested did not. Exposure of the skin to 5% potassium dichromate resulted in an increased, but not propor tionally increased, amount of total Cr concen tration in the skin, compared with exposure to 0.25% potassium dichromate. Exposure to 5% potassium dichromate compared with 2.5% potassium did not result in much more of an increased Cr skin concentration dichromate, indicating a possible limited binding capacity of the skin. A smaller amount of Cr was bound to the skin when the salts were incubated in simulated sweat before application onto the skin. A larger accumulation of Cr was found in the skin after exposure to potassium dichromate compared with Cr(III) compounds. Rudolf et al.  reported a pronounced ef fect of potassium chromate on the morphol ogy and motile activity of human dermal fi broblasts at concentrations ranging from 1.5 to 45 ^M in tissue culture studies. A time and concentration-dependent effect on cell shrink age, reorganization of the cytoskeleton, and inhibition of fibroblast motile activity was re ported. The inhibitory effect on fibroblast m i gration was seen at all concentrations 8 hours after treatment; effects at higher doses were seen by 4 hours after treatment. Cr(VI) expo sure also resulted in oxidative stress, alteration of mitochondrial function, and mitochondriadependent apoptosis in dermal fibroblasts.

# Summary of Animal Studies
Cr(VI) compounds have been tested in animals using many different experimental conditions and exposure routes. Although experimental conditions are often different from occupation al exposures, these studies provide data to as sess the carcinogenicity of the test compounds. Chronic inhalation studies provide the best data for extrapolation to occupational exposure; few have been conducted using Cr(VI) compounds. However, the body of animal studies supports the classification of Cr(VI) compounds as occu pational carcinogens.
The few chronic inhalation studies available demonstrate the carcinogenic effects of Cr(VI) compounds in mice and rats . Animal stud ies conducted using other respiratory routes of administration have also produced positive results with some Cr(VI) compounds. Zinc chromate and calcium chromate produced a statistically significant (P < 0.05) number of bronchial carcinomas when administered via an intrabronchial pellet implantation system . Cr(VI) compounds with a range of solubilities were tested using this system. Although soluble Cr(VI) compounds did produce tumors, these results were not statistically significant. Some lead chromate compounds produced squamous carcinomas, which although not statistically significant may be biologically significant because of the historical absence of this cancer in control rats.
Steinhoff et al.  administered the same total dose of sodium dichromate either once per week or five times per week to rats via intra tracheal instillation. No increased incidence of lung tumors was observed in animals dosed five times weekly. However, in animals dosed once per week, a statistically significant (P < 0.01) tum or incidence was reported in the 1.25 mg/ kg exposure group. This study demonstrates a dose-rate effect within the constraints of the ex perimental design. It suggests that limiting ex posure to high Cr(VI) levels may be important in reducing carcinogenicity. However, quanti tative extrapolation of these animal data to the human exposure scenario is difficult.
Animal studies conducted using nonrespiratory routes of administration have also produced positive results with some Cr(VI) compounds . These studies pro vide another data set for hazard identification.  Crump , Gibb et al. , and EPA . Dose-response data from the Balti more, Maryland chromium chemical produc tion facility were analyzed by Park et al. , K.S. Crump , and Gibb et al. .
The epidemiologic studies of these worker populations are described in the human health effects chapter (see Chapter 4). Goldbohm et al.  discusses the framework necessary to conduct quantitative risk assessments based on epidemiological studies in a structured, transparent, and reproducible manner.
The Baltimore and Painesville cohorts  are the best studies for predicting Cr(VI) cancer risks be cause of the quality of the exposure estimation, large amount of worker data available for anal ysis, extent of exposure, and years of follow-up . NIOSH selected the Baltimore cohort  for analysis be cause it had the greater num ber of lung cancer deaths, better smoking histories, and a more comprehensive retrospective exposure archive.  . These estimates of increased lung cancer risk vary de pending on the data set used, the assumptions made, and the models tested.
Environmental risk assessments of Cr(VI) exposure have also been conducted [ATSDR 2012;EPA 1998EPA , 1999. These analyses assess the risks of nonoccupational Cr(VI) exposure.

# Baltimore Chromate Production Risk Assessments
NIOSH calculated estimates of excess lifetime risk of lung cancer death resulting from oc cupational exposure to chromium-containing mists and dusts  using data from a cohort of chromate chemical produc tion workers . NIOSH de term ined that Gibb et al.  was the best data set available for quantitative risk assess ment because of its extensive exposure assess ment and smoking information, strong statis tical power, and its relative lack of potentially confounding exposures. Several aspects of the exposure-response relationship were exam ined. Different model specifications were used permitting nonlinear dependence on cumula tive exposure to be considered, and the possi bility of a nonlinear dose-rate effect was also investigated. All models evaluated fit the data comparably well. The linear (additive) relative rate model was selected as the basis for the risk assessment. It was among the better-fitting models and was also preferred on biological grounds because linear low-dose extrapolation is the default assumption for carcinogenesis.
There was some suggestion of a negative dose rate effect, (greater than proportional excess risk at low exposures and less than proportion al risk at high exposures but still a monotic re lationship) but the effect was small. Although lacking statistical power, the analyses examin ing thresholds were consistent with no thresh old on exposure intensity. Some misclassification on exposure in relation to race appeared to be present, but models with and without the exposure-race interaction produced a clear ex posure response. Taken together, the analyses constitute a robust assessment of the risk of chromium carcinogenicity.
The excess lifetim e (45 years) risk for lung cancer mortality from exposure to Cr(VI) was estimated to be 255 per thousand workers at the previous OSHA PEL of 52 ^g/m 3 based on the exposure-response estimate for all men in the Baltimore cohort. At the previous NIOSH REL of 1 ^g/m3 for Cr(VI) compounds, the excess lifetime risk was estimated to be 6 lung cancer deaths per 1,000 workers and at the REL of 0.2 ^g/m3 the excess lifetime risk is approxi mately 1 lung cancer death per 1,000 workers.
The data analyzed were from the Baltimore, Maryland cohort previously studied by  and Gibb et al. . The cohort comprised 2,357 men first hired from 1950 through 1974 whose vital status was followed through 1992. The racial makeup of the study population was 1,205 white (51%), 848 non white (40%) and 304 of unknown race (13%). This cohort had a detailed retrospective expo sure assessment that was used to estimate indi vidual worker current and cumulative Cr(VI) exposures across time. Approximately 70,000 both area and personal airborne Cr(VI) m ea surements of typical exposures were collected and analyzed by the employer from 1950 to 1985, when the plant closed. These samples were used to assign, in successive annual peri ods, average exposure levels to exposure zones that had been defined by the employer. These job title estimated exposures were combined with individual work histories to calculate the Cr(VI) exposure of each member of the cohort.
Smoking information at hire was available from medical records for 91 percent of the popula tion, including packs per day for 70 percent of the cohort. The cohort was largely free of other potentially confounding exposures. The mean duration of employment of workers in the co hort was 3.1 years, while the median duration was only 0.39 of a year.
In this study population of 2,357 workers, 122 lung cancer deaths were documented. This mortality experience was analyzed using Pois son regression methods. Diverse models of exposure-response for Cr(VI) were evaluated by comparing deviances and inspecting cubic splines. The models using cumulative smok ing (as a linear spline) fit significantly better in comparison with models using a simple categorical classification (smoking at hire: yes, no, unknown). For this reason, smoking cu mulative exposure imputed from cigarette use at hire was included as a predictor in the final models despite absence of detailed smoking histories. Lifetime risks of lung cancer death from exposure to Cr(VI) were estimated us ing an actuarial calculation that accounted for competing causes of death.
An additive relative rate m odel was selected which fit the data well and which was readily in terpretable for excess lifetime risk calculations: Based on a categorical analysis, the exposurerace interaction was found to be largely due to an inverse trend in lung cancer mortality among whites: an excess in the range 0.03-0.09 m g/m 3-yr of chromium cumulative exposure and a deficit in the range 0.37-1.1 m g/m 3-yr. Park et al.  concluded that a biological basis for the chromium-race interaction was unlikely and that more plausible explanations include, but are not limited to, misclassification of smoking status, misclassification of chro mium exposures, or chance. It is doubtful that confounding factors play an important role, be cause it is unlikely that another causal risk factor is strongly and jointly associated with exposure and race. The asbestos exposure that was present was reported to be typical of industry generally at that time. Some asbestos exposure may have been associated with certain chromium process areas wherein workers were not representative of the entire workforce on race. For this to ex plain a significant amount of the observed lung cancer excess would require relatively high as bestos exposures correlated with Cr(VI) levels for non-white workers. It would not explain the relative deficit of lung cancer observed among white workers with high cumulative Cr(VI) ex posures. Furthermore, no mesothelioma deaths were observed, and the observed lung cancer excess would correspond to asbestos exposures at levels seen only in asbestos manufacturing or processing environments.
Exposure misclassification, on the other hand, is plausible given the well-known disparities in exposure by race often observed in occupa tional settings. In this study, average exposure levels were assigned to exposure zones within which there may have been substantial racerelated differences in work assignments and resulting individual exposures. Race-exposure interactions would inevitably follow. If the ra cial disparity was the result of exposure misclassification, then models without the racechromium interaction term would provide an unbiased estimate of the exposure-response, although less precisely than if race had been taken into account in the processing of air sampling results and in the specification of ex posure zone averages. Park and Stayner  examined the pos sibility of an exposure threshold in the Balti more cohort by calculating different measures of cumulative exposure in which only concen trations exceeding some specified threshold value were summed over time. The best-fitting models, evaluated with the profile likelihood method, were those with a threshold lower than 1.0 ^g/m3, the lowest threshold tested. The test was lim ited by statistical power but estab lished upper confidence limits for a threshold consistent with the observed data of 16 ^g/ m 3 Cr(VI) for models with the exposure-race interaction or 29 ^g/m 3 Cr(VI), for models without the exposure-race interaction. Other models using a cumulative exposure metric in which concentration raised to some power, Xa, is summed over time, found that the best fit corresponded to a = 0.8. If saturation of some protective process were taking place, one would expect a > 1.0. However, statistical power limited interpretation as a = 1.0 could not be ruled out. Analyses in which a cumula tive exposure threshold was tested found the best-fitting models with thresholds of 0.02 m g/m 3-yr (with exposure-race interaction) or 0.3 m g/m 3-yr Cr(VI)(without exposure-race interaction) but could not rule out no thresh old. The retrospective exposure assessment for the Baltimore cohort, although the best avail able for a chromium-exposed population, has limitations that reduce the certainty of nega tive findings regarding thresholds. Neverthe less, the best estimate at this time is that there is no concentration threshold for the Cr(VI)lung cancer effect.
Crump KS  conducted an analysis of a cohort from the older Baltimore plant reported by . The cumulative exposure estimates of  were also used in the risk assessment. From a Poisson regres sion model, the maximum likelihood estimate of fi, the potency parameter (i.e., unit risk), was 7.5 x 10-4 per ^g/m3-yr. Occupational exposure to Cr(VI) for 45 years was estimated to result in 88 excess lung cancer deaths per 1,000 work ers exposed at the previous OSHA PEL and 1.8 excess lung cancer deaths per 1,000 workers exposed at the previous NIOSH REL. Gibb et al.  conducted a quantitative as sessment of the Baltimore production workers reported by , whose exposure was reconstructed by . This cohort was divided into six subcohorts based on their period of hire and length of employment . Gibb et al.  calculated the lifetime respiratory cancer mortality risk estimates for the four subcohorts who were hired before 1960 and had worked in the old facility. The slopes for these subcohorts ranged from 5.1 x 10-3/^g/m 3 to 2.0 x 10-2/^g/m 3 with a geometric mean of 9.4 x 10-3/^g/m 3.

# Painesville Chromate Production Risk Assessments
Crump et al.  calculated estimates of ex cess lifetime risk of lung cancer death resulting from occupational and environmental expo sure to Cr(VI) in a cohort of chromate chemi cal production workers. The excess lifetime (45 years) risk for lung cancer mortality from occupational exposure to Cr(VI) at 1 ^g/m3 (the previous NIOSH REL) was estimated to be approximately 2 per 1,000 workers for both the relative and additive risk models.
The cohort analyzed was a Painesville, Ohio worker population described by . The cohort comprised 493 workers who met the following criteria: first hired from 1940 through 1972, worked for at least 1 year, and did not work in any of the other Cr(VI) facilities owned by the same company, other than the North Carolina plant. The vital status of the cohort was followed through 1997.
All but four members of the cohort were male.
Little information was available on the racial makeup of the study population other than that available from death certificates. Informa tion on potential confounders such as smok ing histories and other occupational exposures was limited, so this information was not in cluded in the mortality analysis. There were 303 deaths, including 51 lung cancer deaths, reported in the cohort. SMRs were signifi cantly increased for the following: all causes combined, all cancers combined, lung cancer, year of hire before 1960, 20 or more years of ex posed employment, and latency of 20 or more years. A trend test showed a strong relationship between lung cancer mortality and cumulative Cr(VI) exposure. Lung cancer mortality was statistically significantly increased for observa tion groups with cumulative exposures greater than or equal to 1.05 m g/m 3-years.
The exposure assessment of the cohort was reported by Proctor et al. . More than 800 Cr(VI) air-sampling measurements from 21 industrial hygiene surveys were identi fied. These data were airborne area samples. Airborne Cr(VI) concentration profiles were constructed for 22 areas of the plant for each month from January 1940 through April 1972. Cr(VI) exposure estimates for each worker were reconstructed by correlating their job titles and work areas with the corresponding area exposure levels for each m onth of their employment. The cumulative exposure and highest average monthly exposure levels were determined for each worker.
K.S. Crump  calculated the risk of Cr(VI) occupational exposure in its analysis of the Mancuso  data. Cr(III) and Cr(VI) data from the Painesville, Ohio plant  were used to justify a conversion factor of 0.4 to calculate Cr(VI) concentrations from the total chromium concentrations pre sented by Mancuso . The cumulative exposure of workers to Cr(VI) (^g/m 3-yr) was used in the analysis. All of the original expo sure categories presented by Mancuso  were used in the analysis, including those that had the greatest cumulative exposure. A sen sitivity analysis using different average values was applied to these exposure categories. U.S. vital statistics data from 1956, 1967, and 1971 were used to calculate the expected numbers of lung cancer deaths. Estimates of excess lung cancer deaths at the previous NIOSH REL ranged from 5.8 to 8.9 per 1,000 workers. Es timates of excess lung cancer deaths at the pre vious OSHA PEL ranged from 246 to 342 per 1.000 workers.
DECOS  used the EPA  data to calculate the additional lung cancer mortality risk due to occupational Cr(VI) exposure. The EPA estimate that oc cupational exposure to 8 ^g/m3 total dust re sulted in an additional lung cancer mortality risk of 1.4 x 10-2 was used to calculate occupa tional risk. It was assumed that total dust con centrations were similar to inhalable dust con centrations because of the small aerodynamic diameters of the particulates. Additional can cer mortality risks for 40-year occupational exposure to inhalable dust were calculated as 4 x 10-3 for 2 ^g/m 3 Cr(VI).
The EPA used the data of Mancuso 

# Other Cancer Risk Assessments
The International Chromium Development Association (ICDA)  used the overall SMR for lung cancer from 10 Cr(VI) studies to assess the risk of occupational exposure to various levels of Cr(VI) exposure. The 10 stud ies evaluated were those selected by Steenland et al.  as the largest and best-designed studies of workers in the chromium produc tion, chromate paint production, and chro mate plating industries. It was assumed that the mean length of employment of all workers was 15 years. Although this assumption may be appropriate for some of the cohorts, for others it is not: the mean duration of employment for the Painesville cohort was less than 10 years, and for the Baltimore cohort it was less than 4 years. Occupational exposures to Cr(VI) were assumed to be 500 |ig/m3, 1,000 |ig/m 3, or 2,000 ^g/m3 TWA. These are very unlikely Cr(VI) ex posure levels. The mean exposure concentra tions in the Painesville cohort were less than 100 ^g/m3 after 1942, and in the Baltimore cohort the mean exposure concentration was 45 ^g/m 3. For these different exposure levels, three different assumptions were tested: (1) the excess SMR was due to only Cr(VI) exposure, ( 2) Cr(VI) exposure was confounded by smok ing or other occupational exposures so that the baseline SMR should be 130, or (3) confounders set the baseline SMR to 160. The investi gators did not adjust for the likely presence of a healthy worker effect in these SMR analyses.
A baseline SMR of 80 or 90 would have been appropriate based on other industrial cohorts and would have addressed smoking differ ences between industrial worker populations and national reference populations . The reference used for expected deaths was the 1981 life-table for males in England and Wales. The lung cancer mortality risk esti mates ranged from 5 to 28 per 1,000 at exposure to 50 |ig/m3 Cr(VI), to 0.1 to 0.6 per 1,000 at exposure to 1 |ig/m3 Cr(VI). The assumptions made and methods used in this risk assessment make it a weaker analysis than those in which worker exposure data at a particular plant are correlated with their incidence of lung cancer.
The excess lung cancer deaths may have been underestimated by at least a factor of 10, given the assumptions used on duration (factor of 1.5-2.0), exposure level (factor of , and healthy worker bias (factor of 1.1-1.2).

# Summary
The data sets of the Painesville, Ohio and Balti more, Maryland chromate production workers provide the bases for the quantitative risk as sessments of excess lung cancer deaths due to occupational Cr(VI) exposure. In 1975, M an cuso presented the first data set of the Paines ville, Ohio workers, which was used for quan titative risk analysis. Its deficiencies included very limited exposure data, information on total chromium only, and no reporting of the expected number of deaths from lung can cer. Proctor et al.  presented more than 800 airborne Cr(VI) measurements from 23 newly identified surveys conducted from 1943 through 1971 at the Painesville plant. These data and the mortality study of  provided the basis for an improved lung cancer risk assessment of the Painesville workers.
In 1979, Hayes presented the first data of the Baltimore, Maryland production facility work ers, which were later used for quantitative risk assessment. In 2000, Gibb and coworkers provided additional exposure data for an im proved cancer risk assessment of the Baltimore workers . NIOSH selected the Gibb et al.  cohort for quantitative risk analysis  rather than the Painesville cohort because of its greater num ber of lung cancer deaths, better smoking his tories, and a more comprehensive retrospective exposure archive .
In spite of the different data sets analyzed and the use of different assumptions, models, and calculations, these risk assessments have esti mates of excess risk that are within an order of magnitude of each other (see Tables 6-1, 6-   analyzed the most complete data sets available on occupational exposure to Cr(VI). These risk assessments estimated excess risks of lung cancer death of 2 per 1,000 workers  and 6 per 1,000 workers , at a working lifetime expo sure to 1 ^g/m3. Park et al.  estimated an excess risk of lung cancer death of approxi mately 1 per 1,000 workers at a steady 45-year workplace exposure to 0.2 ^g/m 3 Cr(VI). Park and Stayner  evaluated the possibil ity of a threshold concentration for lung cancer in the Baltimore cohort. Although a threshold could not be ruled out because of the lim ita tions of the analysis, the best estimate at this time is that there is no concentration threshold for the Cr(VI)-lung cancer effect.    In addition to limiting airborne concentrations of Cr(VI) compounds, NIOSH recommends that dermal exposure to Cr(VI) be prevented in the workplace to reduce the risk of adverse dermal health effects, including irritation, ul cers, skin sensitization, and allergic contact dermatitis.

# Basis for NIOSH Standards
In the 1973 Criteria for a Recommended Stan dard: Occupational Exposure to Chromic Acid, NIOSH recommended that the federal stan dard for chromic acid, 0.1 mg/m3 as a 15-minute ceiling concentration, be retained because of reports of nasal ulceration occurring at concentrations only slightly above this con centration . In addition, NIOSH recom m ended supplem enting the ceiling concentration with a TWA of 0.05 m g/m 3 for an 8-hour workday to protect against possible chronic effects, including lung cancer and liv er damage. The association of these chronic effects with chromic acid exposure was not proven at that time, but the possibility of a correlation could not be rejected .
In the 1975 Criteria for a Recommended Stan dard: Occupational Exposure to Chromium(VI), NIOSH supported two distinct recommended standards for Cr(VI) com pounds . Some Cr(VI) compounds were consid ered noncarcinogenic at that time, including the chromates and bichromates of hydrogen, lithium, sodium, potassium, rubidium, cesium, and ammonium, and chromic acid anhydride. These Cr(VI) compounds were relatively solu ble in water. It was recommended that a 10-hr TWA limit of 25 ^g Cr(VI)/m 3 and a 15-minute ceiling limit of 50 |ig Cr(VI)/m 3 be applied to these Cr(VI) compounds.
All other Cr(VI) compounds were considered carcinogenic . These Cr(VI) compounds were relatively insoluble in water. At that time, NIOSH had a carcinogen policy that called for "no detectable exposure levels for proven carcinogenic substances" . Thus the basis for the REL for carci nogenic Cr(VI) compounds, 1 |ig Cr(VI)/m 3 TWA, was the quantitative lim itation of the analytical m ethod available for m easuring workplace exposures to Cr(VI) at that time.
NIOSH revised its policy on Cr(VI) com pounds in its 1988 Testimony to OSHA on the Proposed Rule on Air Contaminants . NIOSH testified that while insoluble Cr(VI) compounds had previously been dem onstrated to be carcinogenic, there was now sufficient evidence that soluble Cr(VI) com pounds were also carcinogenic. Human studies cited in support of this position included Blair and Mason , Franchini et al. , Royle , Silverstein et al. , Sorahan et al. , and Waterhouse . In addi tion, the animal studies of Glaser et al.  and Steinhoff et al. 

# Evidence for the Carcinogenicity of Cr(VI) Compounds
Hexavalent chrom ium is a w ell-established occupational carcinogen associated with lung cancer and nasal and sinus cancer . NTP identified Cr(VI) compounds as carcinogens in its first report on carcinogens in 1980 . Toxicologic studies, epidemio logic studies, and lung cancer meta-analyses pro vide evidence for the carcinogenicity of Cr(VI) compounds.

# Epidemiologic Lung Cancer Studies
In 1989, the IARC critically evaluated the pub lished epidemiologic studies of chromium compounds including Cr(VI) and concluded that "there is sufficient evidence in humans for the carcinogenicity of chromium com pounds as encountered in the chromate pro duction, chromate pigment production and chromium plating industries" (i.e., IARC cat egory "Group 1" carcinogen) . Results from two recent lung cancer mortality studies of chromate production workers sup port this evaluation . In 2009, an IARC Working Group reviewed and reaffirmed Cr(VI) com pounds as Group 1 carcinogens (lung) . Gibb et al.  conducted a retrospective analysis of lung cancer mortality in a cohort of Maryland chromate production workers. The cohort of 2,357 male workers first employed from 1950 through 1974 was followed until 1992. Workers with short-term employment (i.e., < 90 days) were included in the study group to increase the size of the low exposure group. The mean length of employment was 3.1 years. A detailed retrospective assessment of Cr(VI) exposure based on more than 70,000 personal and area samples (short-term and full-shift) and information about most work ers' smoking habits at hire was available.
Lung cancer standardized mortality ratios in creased with increasing cumulative exposure (i.e., mg CrO3/m 3-years, with 5-year exposure lag)-from 0.96 in the lowest quartile to 1.57  , respectively). SMRs were also significantly increased for year of hire be fore 1960, > 20 years of employment, and > 20 years since first exposure. The tests for trend across increasing categories of cumulative ex posure, year of hire, and duration of employ ment were statistically significant (P < 0.005).
A test for departure of the data from linearity was not statistically significant (x2 goodness of fit of linear model; P = 0.23).

# Lung Cancer Meta-Analyses
Meta-analyses of epidemiologic studies have been conducted to investigate cancer risk in chromium-exposed workers. Most of these studies also provide support for the classifi cation of Cr(VI) compounds as occupational lung carcinogens.
Sjogren et al.  reported a meta-analysis of five lung cancer studies of Canadian and European welders exposed to stainless steel welding fumes. The meta-analysis found an es timated relative risk of 1.94 (95% CI 1.28-2.93) and accounted for the effects of smoking and asbestos exposure. Steenland et al.  reported overall relative risks for specific occupational lung carcino gens identified by IARC, including chromium.
Ten epidemiologic studies were selected by the authors as the largest and best-designed stud ies of chromium production workers, chro mate pigment production workers, and chro mium platers. The summary relative risk for the 10 studies was 2.78 (95% confidence inter val 2.47-3.52; random effects model), which was the second-highest relative risk among the eight carcinogens summarized. Cole and Rodu  conducted meta-analyses of epidemiologic studies published in 1950 or later to test for an association of chromium exposure with all causes of death, and death from malignant diseases (i.e., all cancers com bined, lung cancer, stomach cancer, cancer of the central nervous system , kid ney cancer, prostate gland cancer, leukemia, Hodgkin's disease, and other lymphatohematopoietic cancers). Available papers (n = 114) were evaluated independently by both authors on eight criteria that addressed study quality.
In addition, papers with data on lung cancer were assessed for control of cigarette smoking effects, and papers with data on stomach can cer were assessed for economic status. Fortynine epidemiologic studies based on 84 papers published were used in the meta-analyses.
The number of studies in each meta-analysis ranged from 9 for Hodgkin's disease to 47 for lung cancer. Association was measured by an author-defined "SMR" that included odds ra tios, proportionate mortality ratios, and most often, standardized m ortality ratios. M ortal ity risks were not significantly increased for m ost causes of death. However, SMRs were significantly increased in all lung cancer meta-analyses (sm oking controlled: 26 stud ies; 1,325 deaths; SMR = 118; 95% CI 112 125) (sm oking not controlled: 21 studies; 1,129 deaths; SMR = 181; 95% CI 171-192) (lung cancer-all: 47 studies; 2,454 deaths; SMR = 141; 95% CI 135-147). Stomach can cer m ortality risk was significantly increased only in meta-analyses of studies that did not control for effects of economic status (eco nom ic status not controlled: 18 studies; 324 deaths; SMR = 137; 95% 123-153). The au thors stated that statistically significant SMRs for "all cancer" m ortality were m ainly due to lung cancer (all cancer: 40 studies; 6,011 deaths; SMR = 112; 95% CI 109-115). Many of the studies contributing to the m eta-anal yses did not address bias from the healthy worker effect, and thus the results are likely underestim ates of the cancer m ortality risks. O ther lim itations of these meta-analyses in clude lack of (1) exposure characterization of populations, such as the route of exposure (i.e., airborne versus ingestion); and (2) detail of criteria used to exclude studies based on "no or little chrome exposure" or "no usable data."

# Animal Experimental Studies
Cr(VI) compounds have been tested in ani mals using many different experimental con ditions and exposure routes. Although ex perimental conditions are often different from occupational exposures, these studies provide additional data to assess the carcinogenicity of the test compounds. Chronic inhalation studies provide the best data for extrapolation to oc cupational exposure; few have been conducted using Cr(VI) compounds. However, the body of animal studies support the classification of Cr(VI) compounds as occupational carcinogens.
The few chronic inhalation studies available demonstrate the carcinogenic effects of Cr(VI) compounds in mice and rats . Female mice ex posed to 1.8 m g/m 3 chromic acid mist (2 hours per day, 2 days per week for up to 12 months) developed a significant number of nasal papil lomas compared with control animals . Female mice exposed to a higher dose of chromic acid mist, 3.6 m g/m 3 (30 minutes per day, 2 days per week for up to 12 months) developed an increased, but not statistically significant, num ber of lung adenomas . Glaser et al.  reported a sta tistically significant num ber of lung tumors in male rats exposed for 18 months to 100 ^g/m3 sodium dichromate; no tumors were reported at lower dose levels.
Animal studies conducted using other routes of administration have also produced adverse health effects with some Cr(VI) compounds. Zinc chromate and calcium chromate produced a statistically significant (P < 0.05) number of bronchial carcinomas when administered to rats via an intrabronchial pellet implantation system . Cr(VI) compounds with a range of solubilities were tested using this system. Although some soluble Cr(VI) compounds did produce bronchial carcino mas, these results were not statistically sig nificant. Some lead chromate compounds p ro duced bronchial squamous carcinomas that, although not statistically significant, may be biologically significant because of the absence of this cancer in control rats.
Steinhoff et al.  administered the same total dose of sodium dichromate either once per week or five times per week to male and female rats via intratracheal instillation. No in creased incidence of lung tumors was observed in animals dosed five times weekly. However, in animals dosed once per week, a statisti cally significant tum or incidence was reported in the 1.25 mg/kg exposure group. This study demonstrates a dose-rate effect within the con straints of the experimental design. It suggests that limiting exposure to high Cr(VI) concen trations may be important in reducing carcino genicity. However, quantitative extrapolation of these animal data to the hum an exposure scenario is difficult.
Animal studies conducted using nonrespiratory routes of administration have also pro duced injection-site tumors with some Cr(VI) compounds . These studies provide another data set for hazard identification.
IARC  concluded "there is sufficient evi dence in experimental animals for the carcino genicity of chromium (VI) compounds".

# Basis for the NIOSH REL
The primary basis for the NIOSH REL is the re sults of the Park et al.  quantitative risk assessment of lung cancer deaths of Maryland chromate production workers conducted on the data of Gibb et al. . NIOSH determined that this was the best Cr(VI) data set available for analysis because of its extensive exposure as sessment and smoking information, strong sta tistical power, and its relative lack of potentially confounding exposures . The results of the NIOSH risk assessment are sup ported by other quantitative Cr(VI) risk assess ments (see Chapter 6).
NIOSH selected the revised REL at an excess risk of lung cancer of approximately 1 per 1.000 workers based on the results of Park et al. . Table 7-1 presents the range of risk levels of lung cancer from 1 per 500 to 1 per 100.000 for workers exposed to Cr(VI). Can cer risks greater than 1 per 1,000 are consid ered significant and worthy of intervention by OSHA. This level of risk is consistent with those for other carcinogens in recent OSHA rules . NIOSH has used this risk level in a variety of circum stances, including citing this level as appropri ate for developing authoritative recommenda tions in criteria documents and peer-reviewed risk assessments .
Additional considerations in the derivation of the REL include analytical feasibility and the ability to control exposure concentrations to the REL in the workplace. The REL for Cr(VI) compounds is intended to reduce workers' risk of lung cancer over a 45-year working lifetime.
Although the quantitative analysis is based on lung cancer mortality data, it is expected that reducing airborne workplace exposures will also reduce the nonmalignant respiratory ef fects of Cr(VI) compounds, including irritated, ulcerated, or perforated nasal septa, and other potential adverse health effects.   The available scientific evidence supports the inclusion of workers exposed to all Cr(VI) compounds into this recommendation. All Cr(VI) compounds studied have dem onstrat ed their carcinogenic potential in animal, in vitro, or human studies . Molecular toxicology studies provide additional support for classifying Cr(VI) com pounds as occupational carcinogens.
At this time, there is insufficient data to quan tify a different REL for each specific Cr(VI) compound . Although there are inadequate epidemiologic data to quan tify the risk of hum an exposure to insoluble Cr(VI) compounds, the results of animal stud ies indicate that this risk is likely as great as, if not greater than, exposure to soluble Cr(VI) compounds . Because of the similar mechanisms of action of soluble and insoluble Cr(VI) compounds, and the quan titative risk assessments dem onstrating sig nificant risk of lung cancer death resulting from occupational lifetime exposure to soluble Cr(VI) compounds, NIOSH recommends that the REL apply to all Cr(VI) compounds.
At this time, there are inadequate data to con duct a quantitative risk assessment for work ers exposed to Cr(VI), other than chromate production workers. However, epidemiologic studies demonstrate that the health effects of airborne exposure to Cr(VI) are similar across workplaces and industries (see Chapter 4). Therefore, the results of the NIOSH quantita tive risk assessment conducted on chromate production workers  are be ing used as the basis of the REL for workplace exposures to all Cr(VI) compounds.

# Park et al.  Risk Assessment
NIOSH calculated estimates of excess lifetime risk of lung cancer death resulting from oc cupational exposure to water-soluble chromi um-containing mists and dusts in a cohort of Baltimore, MD chromate chemical production workers . This cohort, origi nally studied by Gibb et al. , comprised 2,357 men first hired from 1950 through 1974, whose vital status was followed through 1992. The mean duration of employment of workers in the cohort was 3.1 years, and the m edian duration was 0.39 year.
This cohort had a detailed retrospective expo sure assessment of approximately 70,000 mea surements, which was used to estimate indi vidual worker current and cumulative Cr(VI) exposures across time. Smoking information at hire was available from medical records for 91% of the population, including packs per day for 70 percent of the cohort. In this study population of 2,357 workers, 122 lung cancer deaths were documented.
The excess working lifetime (45 years) risk es timates of lung cancer death associated with occupational exposure to water-soluble Cr(VI) compounds using the linear risk model are 255 (95% CI: 109-416) per 1,000 workers at 52 Cr(VI)/m 3, 6 (95% CI: 3-12) per 1,000 work ers at 1 |ig Cr(V I)/m 3, and approximately 1 per 1.000 workers at 0.2 ^g Cr(VI)/m 3.

# Crump et al.  Risk Assessment
Crump et al.  analyzed data from the Painesville, Ohio chromate production work er cohort described by .
The cohort comprised 493 workers who met the following criteria: first hired from 1940 through 1972, worked for at least 1 year, and did not work in any of the other Cr(VI) facili ties owned by the same company other than the North Carolina plant. The vital status of the cohort was followed through 1997.
Information on potential confounders (e.g., smoking) and other occupational exposures was limited and not included in the mortality analysis. There were 303 deaths reported, in cluding 51 lung cancer deaths. SMRs were sig nificantly increased for the following: all causes combined, all cancers combined, lung cancer, year of hire before 1960, 20 or more years of exposed employment, and latency of 20 or more years. A trend test showed a strong relationship between lung cancer mortality and cumulative Cr(VI) exposure. Lung cancer mortality was in creased for cumulative exposures greater than or equal to 1.05 mg/m3-years.
The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to water-soluble Cr(VI) compounds at 1 ^g/m3 was approximately 2 per 1.000 (0.00205  for the relative risk model and 0.00216  for the additive risk model), assuming a linear dose response for cumula tive exposure with a 5-year lag.
Quantitative risk assessments of the Baltimore, Maryland and Painesville, Ohio chromate pro duction workers consistently demonstrate sig nificant risk of lung cancer mortality to work ers exposed to Cr(VI) at the previous NIOSH REL of 1 |ig Cr(VI)/m 3. These results justify lowering the NIOSH REL to decrease the risk of lung cancer in workers exposed to Cr(VI). NIOSH used the results of the risk assess ment of Park et al.  as the basis of the current REL because this assessment analyzes the most extensive database of workplace ex posure measurements, including smoking data on most workers.

# Applicability of the REL to All Cr(VI) Compounds
NIOSH recommends that the REL of 0.2 Cr(VI)/m3 be applied to all Cr(VI) compounds.
Currently, there are inadequate data to exclude any single Cr(VI) compound from this recom mendation. IARC  concluded that "there is sufficient evidence in humans for the carci nogenicity of chromium (VI) compounds".
Epidemiologic studies were often unable to iden tify the specific Cr(VI) compound responsible for the excess risk of cancer. However, these stud ies have documented the carcinogenic risk of occupational exposure to soluble Cr(VI). Gibb et al.  and  report ed the health effects of chromate production workers with sodium dichromate being their prim ary Cr(VI) exposure. These studies, and the risk assessments conducted on their data, demonstrate the carcinogenic effects of this soluble Cr(VI) compound. The NIOSH risk assessment on which the REL is based evalu ated the risk of exposure to sodium dichromate .

# Risk Assessment Summary
Although there are inadequate epidemiologic data to quantify the cancer risk of human ex posure to insoluble Cr(VI) compounds, the re sults of animal studies indicate that this risk is likely as great, if not greater than, exposure to soluble Cr(VI) compounds .
The carcinogenicity of insoluble Cr(VI) com pounds has been demonstrated in animal and human studies . Animal stud ies have demonstrated the carcinogenic poten tial of soluble and insoluble Cr(VI) compounds . IARC  concluded that "there is suffi cient evidence in experimental animals for the carcinogencity of chromium (VI) compounds".
Based on the current scientific evidence, NIOSH recommends including all Cr(VI) compounds in the revised REL. There are inadequate data to exclude any single Cr(VI) compound from this recommendation. NIOSH acknowledges that the frequent use of PPE, including respirators, may be required by some workers in environments where air borne Cr(VI) concentrations cannot be con trolled below the REL in spite of implementing all other possible measures in the hierarchy of controls. The frequent use of PPE may be re quired during job tasks for which (1) routinely high airborne concentrations of Cr(VI) exist, ( 2) the airborne concentration of Cr(VI) is un known or unpredictable, and ( 3) job tasks are as sociated with highly variable airborne concentra tions because of environmental conditions or the manner in which the job task is performed.

# Analytical Feasibility of the REL

# Preventing Dermal Exposure
NIOSH recommends that dermal exposure to Cr(VI) be prevented by elimination or substi tution of Cr(VI) compounds. W hen this is not possible, appropriate sanitation and hygiene procedures and appropriate PPE should be used (see Chapter 8). Preventing dermal expo sure is im portant to reduce the risk of adverse dermal health effects, including dermal irri tation, ulcers, skin sensitization, and allergic contact dermatitis. The prevention of dermal exposure to Cr(VI) compounds is critical in preventing skin disorders related to Cr(VI).

# Summary
NIOSH determined that the data of Gibb et al.  is the most comprehensive data set available for assessing the health risk of oc cupational exposure to Cr(VI), including an extensive exposure assessment database and smoking information on workers. The revised REL is a health-based recommendation derived from the results of the NIOSH quantitative risk assessment conducted on these human health effects data . Other consid erations include analytical feasibility and the achievability of engineering controls.
NIOSH recommends a REL of 0.2 ^g Cr(VI)/ m 3 for an 8-hr TWA exposure within a 40-hr workweek, for all airborne Cr(VI) compounds. The REL is intended to reduce workers' risk of lung cancer over a 45-year working life time. The excess risk of lung cancer death at the revised REL is approximately 1 per 1,000 workers. NIOSH has used this risk level in other authoritative recommendations in crite ria documents and peer-reviewed risk assess ments. Results from epidemiologic and toxico logic studies provide the scientific evidence to classify all Cr(VI) compounds as occupational carcinogens and support the recommendation of having one REL for all Cr(VI) compounds [NIOSH 1988b[NIOSH , 2002[NIOSH , 2005a.
Exposure to Cr(VI) compounds should be eliminated from the workplace where pos sible because of the carcinogenic potential of these compounds. Where possible, less-toxic compounds should be substituted for Cr(VI) compounds. Where elimination or substitution of Cr(VI) compounds is not possible, attempts should be made to control workplace exposures below the REL. Compliance with the REL for Cr(VI) compounds is currently achievable in some industries and for some job tasks. It may be difficult to achieve the REL during certain job tasks including welding, electroplating, spray painting, and atomized-alloy spray-coat ing operations. Where airborne exposures to Cr(VI) cannot be reduced to the REL through using state-of-the-art engineering controls and work practices, the use of respiratory protec tion will be needed.
The REL may not be sufficiently protective to prevent all occurrences of lung cancer and other adverse health effects among workers exposed for a working lifetime. NIOSH there fore recommends that worker exposures be maintained as far below the REL as achievable during each work shift. NIOSH also recom mends that a comprehensive safety and health program be implemented that includes worker education and training, exposure monitoring, and medical monitoring.
In addition to controlling airborne exposures at the REL, NIOSH recommends that dermal exposures to Cr(VI) compounds be prevented to reduce the risk of adverse dermal health ef fects, including dermal irritation, ulcers, skin sensitization, and allergic contact dermatitis. In addition to limiting airborne concentra tions of Cr(VI) compounds, NIOSH recom mends that dermal exposure to Cr(VI) be prevented in the workplace to reduce the risk of adverse dermal health effects, including irritation, ulcers, allergic contact dermatitis, and skin sensitization.

# Risk Management

# Sampling and Analytical Methods
The sampling and analysis of Cr(VI) in work place air should be performed using precise, ac curate, sensitive, and validated methods. All signs should be printed both in English and in the language(s) of non-English-speaking workers. All workers who are unable to read should receive oral instruction on the content and instructions on any written signs. Signs using universal safety symbols should be used wherever possible.

# Exposure Control Measures
Many exposure control measures are used to protect workers from potentially harmful ex posures to hazardous workplace chemical, physical, or biological agents. These control measures include, in order of priority: elimina tion, substitution, engineering controls, ad m inistrative controls and appropriate work practices, and the use of protective clothing and equipment . The occupa tional exposure routes of prim ary concern for Cr(VI) compounds are the inhalation of air borne Cr(VI) and direct skin contact. This sec tion provides information on general exposure control measures that can be used in many workplaces and specific control measures for controlling Cr(VI) exposures that are effective in some workplaces.

# Elimination and Substitution
Elimination of a hazard from the workplace is the most effective control to protect worker health. Elimination may be difficult to imple ment in an existing process; it may be easier to implement during the design or re-design of a product or process.
If elimination is not possible, substitution is the next choice of control to protect worker health. Using substitution as a control measure may include substitution of equipment, mate rials, or less hazardous processes. Equipment substitution is the most common type of sub stitution . It is of ten less costly than process substitution, and it may be easier than finding a suitable substitute material. An example that applies to Cr(VI) ex posure reduction is the substitution of an en closed and automated spray paint booth for a partially enclosed workstation.
Material substitution is the second most com mon type of substitution after equipment sub stitution. It has been used to improve the safety of a process or lower the intrinsic toxicity of the material being used. However, evaluation of the potential adverse health effects of the substitute material is essential to ensure that one hazard is not replaced with a different one . Blade et al.  reported material substitu tion in some processes with potential worker exposures to Cr(VI) compounds investigated by NIOSH between 1999 and 2001. A reduc tion in the use of chromate-containing paints was reported in construction (i.e., bridge re painting) and vehicle manufacturing (i.e., the manufacture of automobiles and most trucks reportedly no longer uses chromate paints). However, chromate-containing paints report edly remained without satisfactory substi tute in aircraft manufacture and refurbishing. Chromium electroplating industry represen tatives also reported steady demand for hard chrome finishes for mechanical parts such as gears, molds, etc., because of a lack of econom ical alternatives for this durable finish.
Many examples of process substitution have been considered. A change from an interm it tent or batch-type process to a continuous-type process often reduces the potential hazard, par ticularly if the latter process is more automat ed .
Dipping objects into a coating material, such as paint, usually causes less airborne material and is less of an inhalation hazard than spray ing the material.
Reducing the Cr(VI) Content o f Portland Ce m ent. One example of substitution is using Portland cement with a reduced Cr(VI) con tent to reduce workers' risk of skin sensitiza tion. The trace amount of Cr(VI) in cement can cause allergic contact dermatitis that can be debilitating and marked by significant, long-term adverse effects . The chromium in cement can originate from a va riety of sources, including raw materials, fuel, refractory brick, grinding media, and additions . The manufacturing process, including the kiln conditions, deter mines how much Cr(VI) forms. The Cr(VI) content of cement can be lowered by using materials with lower chromium content dur ing production and/or by adding agents that reduce Cr(VI). The use of slag, in place of or blended with clinker, may decrease the Cr(VI) content . Fer rous sulfate is the material most often added to cement to reduce its Cr(VI) content.  . Limiting the Cr(VI) content of cement in the United States warrants consideration. Further research on the potential impacts of this change in U.S. in dustry is needed.

# Engineering Controls
If elimination or substitution are not possible, engineering controls are the next choice for re ducing worker exposure to Cr(VI) compounds. These controls should be considered when new facilities are being designed or when existing facilities are being renovated to maximize their effectiveness, efficiency, and economy. Engi neering measures to control potentially hazard ous workplace exposures to Cr(VI) compounds include isolation and ventilation. OSHA deter mined that the primary engineering control measures most likely to be effective in reduc ing employee exposure to airborne Cr(VI) are local exhaust ventilation (LEV), process enclo sure, process modification, and improved gen eral dilution ventilation . These and other engineering controls are described in the following sections.

# Isolation
Isolation as an engineering control may in volve the erection of a physical barrier between the worker and the hazard. Isolation may also be achieved by the appropriate use of distance or time . Examples of hazard isola tion include the isolation of potentially hazard ous materials into separate structures, rooms, or cabinets; and the isolation of potentially hazardous process equipment into dedicated areas or rooms that are separate from other work areas . Sepa rate ventilation of the isolated area(s) may be needed to maintain the isolation of the hazard from the rest of the facility . Com plete isolation of an entire process also may be achieved using automated, remote operation methods .
An example of an isolation technique to con trol Cr(VI) exposure is the use of a separate, ventilated m ixing room for m ixing batches of powdered m aterials containing chromate pigments.

# Ventilation
Ventilation may be defined as the strategic use of airflow to control the environment within a space-to provide thermal control within the space, remove an air contaminant near its source of release into the space, or dilute the concentration of an air contaminant to an ac ceptable level . W hen controlling a workplace air contaminant such as Cr(VI), a specific dedicated exhaust ventilation system or assembly might need to be designed for the task or process .
Local exhaust ventilation (LEV) is primarily intended to capture the contaminant at spe cific points of release into the workroom air through using exhaust hoods, enclosures, or similar assemblies. LEV is appropriate for the control of stationary point sources of contami nant release. It is important to assure proper selection, maintenance, placement, and opera tion of LEV systems to ensure their effective ness .
General ventilation, often called dilution venti lation, is primarily intended to dilute the con centration of the contam inant w ithin the general workroom air. It controls widespread problems such as generalized or mobile emission sources . Whenever practicable, point-source emissions are most ef fectively controlled by LEV, which is designed to remove the contaminant at the source be fore it emanates throughout the workspace. Dilution ventilation is less effective because it merely reduces the concentration of the con taminant after it enters the workroom air, rath er than preventing much of the emitted con taminant from ever entering the workroom air.
It also is much less efficient, requiring much greater volumetric airflow to reduce concen trations. However, for non-point sources of contaminant emission, dilution ventilation may be necessary to reduce exposures.
The air exhausted by a LEV system must be re placed, and the replacement air will usually be supplied by a make-up air system that is not as sociated with any particular exhaust inlet and/ or by simple infiltration through building open ings (relying on infiltration for make-up air is not recommended). This supply of replacement air will provide general ventilation to the space even if all the exhaust is considered local. The designation of a particular ventilation system or assembly as local or general, exhaust or sup ply, is governed by the prim ary intent of the de sign .
Push-pull ventilation may be used to control exposures from open surface tanks such as elec troplating tanks. Push-pull ventilation includes a push jet located on one side of a tank and a lateral exhaust hood on the other side . The jet formed over the tank surface cap tures the emissions and carries them into the hood. Many other types of ventilation systems may be used to control exposures in specific workplace operations .

# Examples of engineering controls to reduce Cr(VI) exposures
Many types of engineering controls have been used to reduce workplace Cr(VI) exposures. Some of the engineering controls recommend ed by NIOSH in 1975 are still valid and in use today. Some examples are in cluded here, there are many others .
Closed systems and operations can be used for many processes, but it should be ensured that seals, joints, covers, and similar assemblies fit properly to maintain negative static pressure within the closed equipment, relative to the surroundings.
The use of LEV may be needed even with closed systems to prevent workers' exposures during operations such as unloading, charging, and packaging. The use of protective clothing and equipment may also be needed. Ventila tion systems should be regularly inspected and maintained to assure effective operation. Work practices that may obstruct or interfere with ventilation effectiveness must be avoided. Any modifications or additions to the ventilation system should be evaluated by a qualified pro fessional to ensure that the system is operating at design specifications.
The use of clean areas, such as control rooms supplied with uncontaminated air, is one m ethod of isolating the workers from the haz ard. An area to which workers may retreat for periods of time when they are not needed at the process equipment also may be configured as a clean area.  . Qualitative airflow visualization using smoke tubes suggested that the push-pull ventilation systems were generally effective in moving air away from workers' breathing zones. How ever, maintenance problems with the ventila tion system suggested that the system was not always operating effectively. Floating plastic balls had reportedly been used in the past but proved impractical. M ist suppressants that reduce surface tension were not used because of concerns that they may induce pitting in the hard chrome-plated finish.
In contrast with hard chrome plating tanks, control of bright chrome plating tank emis sions is less problematic. Bright chrome plat ing provides a thin chromium coating for appearance and corrosion protection to n on mechanical parts. The use of a wetting agent as a fume suppressant that reduces surface tension provided effective control of emis sions .
At another facility, a hard chrome-plating tank was equipped with a layer of a newly devel oped, proprietary viscous liquid and a system to circulate it . This system effectively reduced mist emission containing Cr(VI) from the tank, but it was not durable.
Welding and therm al cutting involving chro m ium -containing metals. Many welding task variables affect the Cr(VI) content of weld ing fume and the associated Cr(VI) expo sures. Both the base metal of the parts being joined and the consumable metal (welding rod or wire) added to create the joint have vary ing compositions of chromium. The welding process and shield-gas type, and the Cr con tent of both the consumable material and the base metal affect the Cr(VI) content of the fume . W hen pos sible, process and material substitution may be effective in reducing welding Cr(VI) expo sures. Evaluation of an exposure database from The Welding Institute indicated that welding of stainless steel or Inconel (a nickel-chromium alloy containing 14-23% Cr ) resulted in median Cr(VI) exposures of 0.6 ^g/m 3 com pared with the Cr(VI) exposures of the weld ing of other metals, which were less than the LOD (range 0.1-0.2 |ig/m3) . Processes such as gas-tungsten arc weld ing (GTAW), submerged arc welding (SAW), and gas-metal arc welding (GMAW) tend to generate less fume . Whenever appropriate, the selection of GTAW will help to minimize Cr(VI) exposures in welding fume . Cr(VI) exposures during shielded-metal arc welding (SMAW) may be minimized by using consumables (welding rod or wire) containing low chromium con tent (i.e., less than 3% Cr) .
Welding or thermal-cutting fumes containing Cr(VI) are often controlled using LEV systems . Two common LEV systems are high-volume low-vacuum systems or lowvolume high vacuum systems. High-volume low-vacuum systems have large-diameter hos es or ducts that result in larger capture distanc es . High-vacuum low-volume sys tems use smaller hoses and so have a smaller capture distance; they are often more portable . In controlled welding trials, the use of a portable high-vacuum fume extraction unit reduced Cr(VI) exposures from a median of 1.93 ^g/m 3 to 0.62 ^g/m3 (P = 0.02) .
When welding outdoors, the effect of the wind and the position of the welder are important factors controlling the effectiveness of LEV . In the field setting LEV ef fectiveness is directly related to proper usage . Proper positioning of the ventilation inlet relative to the welding nozzle and the worker's breathing zone is critical to exposure-control performance; this often requires frequent repositioning by the weld er . Welders may keep the LEV inlet too far from the weld site to be effective, or they may be reluctant to use the LEV system because of concerns that the incoming venti lation air could adversely affect the weld qual ity by impairing flux or shield-gas effective ness .
Specialized systems called "fume extraction welding guns" can be used in many workplaces (e.g., outdoors) to reduce worker exposure to welding fumes. These systems combine the arc-welding gun with a series of small LEV air inlets so that the air inlets are always at a close distance to the welding arc. These systems are heavier and more cumbersome than standard arc-welding guns, so ergonomic issues must be considered .
Spray application of chromate-containing paints. Blade et al.  determined that the most ef fective measure for reducing workers' Cr(VI) exposures at a facility where chromate-containing paints were applied to aircraft parts would be the substitution of paints with lower chromate content (i.e., 1% to 5%) for those with higher content (i.e., 30%) wherever pos sible . Results indicated that partially enclosed paint booths for large-part painting might not provide adequate con taminant capture. The facility also used fully enclosed paint booths with single-pass ventila tion, with air entering one end and exhausted from the other. The average internal air veloci ties within these booths needed to exceed the speed with which the workers walked while spraying paint so that the plume of paint over spray moved away from the workers.
Removal o f chromate-containingpaints. At a construction site where a bridge was to be re painted, the removal of the existing chromatecontaining paint was accomplished by abrasive blasting. An enclosure of plastic sheeting was constructed to contain the spent abrasive and paint residue and prevent its release into the sur rounding environment . No mechanical ventilation was provided to the con tainment structure. NIOSH recommended that this type of containment structure be equipped with general-dilution exhaust ventilation that discharges the exhausted air through a high efficiency particulate air (HEPA) filtration unit.
Other types of specialized engineering mea sures applicable for the control of exposures during chromate-paint removal have been in vestigated and recommended for selected ap plications. These recommendations are often made in the context of lead exposure control , but they are relevant to Cr(VI) control because lead chromate paints may be encountered during paint removal projects. Such control measures include high-pressure water blasting, wet-abrasive blasting, vacuum blasting, and the use of remotely controlled automated blasting devices . High-pressure water blasting uses a blast of extremely focused water at high veloc ity to remove paint and corrosion, but it does not reprofile the underlying metal substrate for repainting. Wet-abrasive blasting uses a con ventional blasting medium that is wetted with water to remove the paint and corrosion and to reprofile the metal. The wetted medium helps suppress the emission of dust that contains re moved chromate-paint particles. Vacuum blast ing uses a blasting nozzle surrounded by a vacu um shroud with a brush-like interfacing surface around its opening, which the operator keeps in contact with the metal surface being blast ed. Large reductions in exposures have been reported with this system, but considerations include the following: good work practices are needed to assure proper contact with the sur face is maintained; the full assembly is heavier than conventional nozzles and thus raises er gonomic concerns; and production (removal) rates reportedly are much lower than with con ventional blast nozzles .
M ixing o f chromate-containing pigments. At a colored-glass manufacturing facility, pigments containing Cr(VI) were weighed in a separate room with LEV, then moved to a production area for mixing into batches of materials . Cr(VI) exposures at the facility were very low to not detectable.
At a screen printing ink manufacturing facil ity, there was no dedicated pigment-mixing room; LEV was used at the ink-batch mixing and weighing operation, but capture velocities were inadequate . Almost all the Cr(VI) exposures of the ink-batch weigh ers exceeded the existing REL.
Operations creating concrete dust. Portland ce ment contains Cr(VI), so operations that cre ate concrete dust have the potential to expose workers to Cr(VI). In one operation studied by NIOSH, the use of water to suppress dust dur ing cleanup was observed to result in visibly lower dust concentrations . All Cr(VI) exposures at the facility were low. At a construction-rubble crushing and recycling facil ity, a water-spray system was used on the crusher at various locations, and the operator also used a hand-held water hose . All Cr(VI) exposures at this facility also were low.

# Employer Actions
The employer should ensure that the qualified health care provider's recommended restric tion of a worker's exposure to Cr(VI) com pounds or other workplace hazards is followed, and that the REL for Cr(VI) compounds is not exceeded without requiring the use of PPE. Ef forts to encourage worker participation in the medical monitoring program and to report any symptoms promptly to the program di rector are important to the program's success. Medical evaluations perform ed as part of the medical monitoring program should be pro vided by the employer at no cost to the partici pating workers. Where medical removal or job reassignment is indicated, the affected worker should not suffer loss of wages, benefits, or seniority.
The employer should ensure that the pro gram director regularly collaborates with the employer's safety and health personnel (e.g. industrial hygienists) to identify and control work exposure and activities that pose a risk of adverse health effects.

# Smoking Cessation
Smoking should be prohibited in all areas of any workplaces in which workers are exposed to Cr(VI) compounds. As cigarette smoking is an important cause of lung cancer, NIOSH recommends that smoking be prohibited in the workplace and all workers who smoke par ticipate in a smoking cessation program. Em ployers are urged to establish smoking cessa tion programs that inform workers about the hazards of cigarette smoking and provide as sistance and encouragement for workers who want to quit smoking. These programs should be offered at no cost to the participants. Infor mation about the carcinogenic effects of smok ing should be disseminated. Activities prom ot ing physical fitness and other health lifestyle practices that affect respiratory and overall health should be encouraged through training, employee assistance programs, and/or health education campaigns.

# Record Keeping
Employers should keep employee records on exposure and medical monitoring according to the requirements of 29 CFR 1910.20(d), Pres ervation of Records.
Accurate records of all sampling and analysis of airborne Cr(VI) conducted in a workplace should be maintained by the employer for at least 30 years. These records should include the name of the worker being monitored; Social Security number; duties perform ed and job locations; dates and times of measurements; sampling and analytical methods used; type of personal protection used; and number, dura tion, and results of samples taken.
Accurate records of all medical monitoring conducted in a workplace should be m ain tained by the employer for 30 years beyond the employee's termination of employment. Any half mask particulate air-purifying respirator with a N100*, R100, or P100 filter worn in combination with eye protection.
If chromyl chloride is present, any half mask air-purifying respirator with can isters providing organic vapor (OV) and acid gas (AG) protection with a N100, R100, or P100 filter worn in combination with eye protection.
Any supplied-air respirator with loose-fitting hood or helmet operated in a continuous-flow mode; any powered air-purifying respirator (PAPR) with a HEPA filter with loose-fitting hood or helmet.
If chromyl chloride is present, any PAPR providing OV and AG protec tion with a HEPA filter with loose-fitting hood or helmet.
Any full facepiece particulate air-purifying respirator with a N100, R100, or P100 filter; any PAPR with full facepiece and HEPA filter; any full facepiece supplied-air respirator operated in a continuous-flow mode.
If chromyl chloride is present, any full facepiece air-purifying respirator pro viding OV and AG protection with a N100, R100, or P100 filter; any full face piece PAPR providing OV and AG protection and a HEPA filter.
Any supplied-air, pressure-demand respirator with full facepiece.
Any self-contained breathing apparatus that is operated in a pressure-demand or other positive-pressure mode, or any supplied-air respirator with a full fa cepiece that is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained positive-pressure breathing apparatus.
Any self-contained breathing apparatus that has a full facepiece and is oper ated in a pressure-demand or other positive-pressure mode.
Any air-purifying, full-facepiece respirator with a N100, R100, or P100 filter or any appropriate escape-type, self-contained breathing apparatus.
If chromyl chloride is present, any full facepiece gas m ask (14G) with a canis ter providing OV and AG protection with a N100, R100, or P100 filter or any appropriate escape-type, self-contained breathing apparatus.
Abbreviations: AG= acid gas; APF = assigned protection factor; Cr(VI) = hexavalent chrom ium ; HEPA = high efficiency particulate air; IDLH = im mediately dangerous to life or health; OV=organic vapor; PAPR = powered air-purifying respirator. fThe protection offered by a given respirator is contingent upon (1) the respirator user adhering to complete program requirem ents (such as those required by OSHA in 29 CFR 1910.134), ( 2) the use of NIOSH-certified respirators in their approved configuration, and (3) individual fit testing to rule out those respirators with tight-fitting facepieces that cannot achieve a good fit on individual workers. *N-100 series particulate filters should n o t be used in environm ents w here there is potential for exposure to oil mists.

# INTRODUCTION History of Hexavalent Chromium Hazard
Chromium is commercially important in metallurgy, electroplating, and in diverse chemical ap plications such as pigments, biocides and strong oxidizing agents. Adverse health effects have long been known and include skin ulceration, perforated nasal septum, nasal bleeding, and conjuncti vitis. Reports of bronchogenic carcinoma appeared prior to World War II in Germany and were subsequently confirmed in multiple studies.1 The International Agency for Research on Cancer (IARC) declared in 1980 that chromium and certain of its compounds are carcinogenic and, in 1987, concluded that hexavalent chromium is a hum an carcinogen but that trivalent chromium was not yet classifiable. Recent studies updating chromium worker cohorts in Ohio2,3 and Marylandi demonstrated an excess lung cancer risk from exposure to hexavalent chromium.

# Regulation of Chromium Exposures
The current Permissible Exposure Limit (PEL) of the U.S. O ccupational Safety and Health A dm inistration (USHA) is 0.1 mg/m3 for soluble hexavalent chrom ium (as CrU3) as an 8 hour time-weighted average. 4 The American Conference of Governmental Industrial Hygienists has a similar recommendation.5 The U.S. National Institute for Occupational Safety and Health recom mends a limit of 0.001 m g/m 3 (as Cr).6 Due to continuing concerns over lung cancer risks from hexavalent chromium, OSHA is currently reviewing the distribution of chromium exposures in the U.S. workforce and the available estimates of excess risk.

# Present Objective
The goal of this investigation was to evaluate various models of exposure-response for lung cancer mortality and exposure to hexavalent chromium compounds and then conduct a risk assessment for lung cancer based on these models. The cohort of chromate workers analyzed by Hayes et al.7 and later updated and modified by Gibb et al.1 was used for the analysis. In addition to a detailed retrospective exposure assessment for chromium, this cohort had smoking information and is be lieved to be largely free of other potentially confounding exposures from this plant. Using logtransformed cumulative exposure estimates within a proportional hazards regression model, Gibb et al. observed the rate of lung cancer mortality in these chromate workers to increase by a factor of 1.38 for each 10-fold increase in cumulative exposure to hexavalent chromium (p=0.0001).i

# METHODS
The description of the cohort can be found in Gibb et al. and comprised 2372men hired between August 1, 1950and December 31, 1974 at a plant in Baltimore, MD.1,7 Fifteen workers lost to followup were excluded, leaving 2357 subjects for analysis. Followup began with date of hire and con tinued until December 31, 1992 or the date of death, whichever occurred first. The cohort consisted of 1205 men known to be white (51%), 848 known to be nonwhite (36%)-believed to be mostly African Americans-and 304 with unknown race (13%). The mean duration of employment was 3.1 yr., but the median was 0.39 yr. Some smoking information was available at hire for 91% of the study population, including smoking level in packs per day for 70%. For those of unknown smok ing status (9%), average levels were assigned; for known cigarette smokers with unknown cigarette usage (21%), the average level among known smokers was assigned. Cumulative smoking expo sure, as packs/day-years, was calculated assuming workers smoked from age 18 until the end of followup, and using a 5 year lag (same as for chromium exposure).

# Chromium Exposure History
This chromate manufacturing facility began operation in 1845 and continued until 1985. Because of facility and process changes and the limited availability of detailed early air sampling data, the study population was restricted to those who worked in the "new" plant and were hired between August 1, 1950 andDecember 31, 1974. A detailed retrospective exposure assessment was con ducted for this populationi using contemporaneous exposure measurements. During 1950-61, short-term personal samples were collected using high volume pumps. From 1961 until 1985 ap proximately 70,000 systematic area air samples were collected at 154 fixed sites (27 sites after 1977). Based on these air samples and recorded observations of the fraction of time spent in these exposure zones by each job title, the employer calculated exposures by job title. After 1977, fullshift personal samples were collected as well. Hexavalent chromium concentrations (as CrU3) were based on laboratory determinations of water-soluble chromate perform ed by the employer; results of the area sampling/time-in-zone system of calculating exposures were adjusted to the personal sample results. Exposure histories were then calculated for each worker based on the jobs held (defined by dates) and corresponding hexavalent chromium exposure estimate for that job title and time period. Total cumulative exposures to hexavalent chromium averaged 0.134 m g/m 3-yr, with a maximum value of 5.3 mg/m3-yr.1

# Mortality Analyses
A classification table for Poisson Regression analysis was calculated using a FORTRAN program developed previously8 which classified followup in 16 age (<20, 20-24, 25-29, 30-34,... , 85+), 9 calendar (1950-54, 1955-59,...1990-94), and three race categories (0=nonwhite, 1=white, 2= unknown), together with 50 levels of time-dependent cumulative hexavalent chromium exposure and 10 levels of time-dependent cumulative smoking exposure and employment duration. The 50 intervals of cumulative exposure were defined to be narrower at the low exposure end compared to the high end because observation time was concentrated at the low end. Although classified in dis crete levels, cumulative exposures for chromium and smoking were entered into regression models as a continuous variable defined by the person-year weighted mean values of cumulative exposure in each of the classification strata. Cumulative exposure is a standard metric used in modeling car cinogenic risk in human populations. The unit of followup in this procedure was 30 days, i.e., every 30-day interval of a worker's observed person-time (and lung cancer death outcome) was classified as described above. To address latency, different lag periods were used and, for some analyses, cu mulative exposures were calculated in three time periods: 5-9.99, 10-19.99, 20 or more years prior to observation.
Relative rate models of the following forms (1a-1f) were evaluated for the effect of cumulative chromium exposure on lung cancer mortality: where, a0 (intercept), a, a1, and a2 are parameters to be estimated.

# Log-linear models
External standardization on age, race and calendar time was accomplished using U.S. rates for lung cancer mortality during 1950-1994 9 as a multiplier of person-years. This approach makes use of well-known population rates and yields models of standardized rate ratios in which the intercept is an estimate of the (log) standardized mortality ratio (SMR) for workers without chromium or smoking exposures. The m ethod permits departures from the reference rates by including explicit terms (e.g., age or race) in the model, and it enables internal comparisons on exposure. Those with unknown race (n=304) were assigned a composite expected rate as a weighted average of the exter nal race-specific rates based on the distribution of race in their year of hire.
Poisson regression models were fit using Epicure software.10 Descriptive categorical analyses for chromium exposure-response were conducted using five levels of cumulative exposure defined to produce equal numbers of lung cancer cases in the upper levels for both races combined. The lowest category encompassed the most observation time and observed deaths because of the large num ber of short duration employees in this study population (median duration: 4.7 mos.). Files were also constructed for Cox proportional hazards models with continuous cumulative exposures and risk sets based on the attained age of the lung cancer case at death. Results using Cox propor tional hazard analyses were similar to the Poisson analyses and are not shown.
The models with the largest decrease in deviance (i.e., decrease in -2log (likelihood) with addi tion of exposure terms) were considered to be the "best" fitting. The adequacy of the parametric forms for exposure and for smoking duration in these models was also investigated by fitting cubic splines11. The spline models were fit as generalized additive models with three degrees of freedom for the effect of exposure using S-Plus, version 4.5. 12 Unlagged and lagged cumulative exposures were considered. Models with exposures lagged by 5 yrs or 10 yrs provided statistically equivalent fits to the data (based on minimizing the deviance) which were better than that obtained with the unlagged model; a 5 yr lag was chosen to conform to previ ous analyses of this cohort.1 The cumulative smoking variable was included in the log-linear or linear terms of different models. However, in estimating the chromium effect for calculating excess lifetime risk, the smoking variable was placed in the loglinear term in order to produce a chromium risk esti mate relative to an unexposed population without regard to smoking status. Finally, to better model the smoking exposure-response, a piece-wise linear spline was used with a knot chosen at 30 packs/ day-yrs). This choice was motivated by a cubic spline analysis of the smoking effect exhibiting a pla teau above 30 pack-years. The final model chosen for estimating excess lifetime lung cancer risk had the following form, consisting of the product of "loglinear" and "linear" terms:
Rate =  x  where: Ind() are indicators of race (white or unknown), Smk1 and Smk2 are variables speci fied for the piece-wise linear terms on cumulative smoking, and CumCr6 is cumulative hexavalent chromium exposure.

# Estimation of Working Lifetime Risks
Excess lifetime risk of death from lung cancer was estimated for a range of chromium air concen trations using an actuarial m ethod that accounts for competing risks and was originally developed for a risk analysis of radon.13 Excess lifetime risk was estimated by first applying cause-specific rates from an exposure-response model to obtain lifetime risk, and then subtracting the same expression with exposures set to zero:
Excess lifetime risk = Zi {  x S(X,i) x  } -Zi {  x S(0,i) x 
where R+i (X)= all cause age-specific m ortality rate for exposed population; qi = Pr(death in year i given alive at the start of year i); and S(X,i) = (1-q1) x (1-q2) x ... x (1-qi 1), probability of survival to year i For specified hexavalent chromium concentrations, excess lifetime risks were estimated making the assumption that workers were occupationally exposed to constant concentrations between the ages of 20 and 65, or 45 years (less if dying before age 65). Annual excess risks were accumulated up to age 85; risk among those surviving past age 85 was not calculated because of small numbers and unstable rates. Rate ratios for lung cancer mortality corresponding to work at various chromium concentrations were derived from the final linear relative rate Poisson regression model. Agespecific all-cause death rates came from a life table for the U.S. population.14

# RESULTS

# Lung Cancer Mortality
Lung cancer was the underlying cause for 122 deaths in the chromate cohort. Fitting a Poisson regression model with indicator terms for race produced similar lung cancer SMRs for white (SMR=1.85, 95%CI=1.45-2.31) and nonwhite (SMR=1.87, 95%CI=1.39-2.46) workers that were close to those reported by Gibb et al. (1.86,1.88, respectively, using different reference rates).i
Results from fitting models with five categorical chromium exposure levels and unadjusted for smoking reveal a clear upward trend for the lung cancer SMR with cumulative chromium exposure but the trends differed by race (Table 1). The same patterns were observed using internally stan dardized rate ratios (SRRs, Table 1). The nonwhite workers exhibited a strong overall increasing trend of lung cancer risk except for a deficit in the 2nd exposure category (based on two deaths). The white workers exhibited an erratic exposure-response relationship, with elevated risks in the 1st, 2nd and 5th categories, but a declining trend across the 2nd, 3rd and 4th categories.
Initially several specifications of exposure-response were examined within the family of log-linear models: 1a-1d above. Models with linear, square root, quadratic and log-transformed representa tions of cumulative chromium exposure performed about the same (Table 2, models 1-3,4.1) but a model in which smoking cumulative exposure was log-transformed performed considerably bet ter (Table 2, model 4.2). Use of a piece-wise linear specification for smoking exposure resulted in further improvement (Table 2 , model 4.3). For a saturated model containing both the logtransform ed and piece-wise linear smoking terms, the model deviance was almost identical to that with the piece-wise term s alone (1931.39 vs. 1931.57). Cubic splines applied to cumulative chromium exposure in log-linear models did not detect significant smooth departures from any of the specified models.
(X2=10.6, p=0.001) (Table 4, m odel 1 vs. 2). This interaction was observed w hether age, race and calendar tim e were adjusted by stratification (internal adjustm ent) or by using external population rates. The chromium exposure-response for white men was diminished with the in teraction (RR=1.18, 95% CI=0.43-1.92, for 1 mg/m3-yr cumulative exposure) but an overall lung cancer excess remained for that group.
Cumulative smoking was used in the final models despite absence of detailed smoking histories because, in comparison with models using a simple categorical classification (smoking at hire: yes, no, unknown), the models using cumulative smoking fit better. The changes in -2ln(Likelihood) for the cumulative smoking piece-wise linear terms versus the categorical terms (both with two degrees of freedom) were 28.42 and 25.83 respectively in the final model.
A significant departure of the estimated background rate (for unexposed workers) from the U.S. reference rate was observed with age and with race, but not with calendar time. The age effect corre sponded to a reduction of 8-10% (RR=0.92, 0.90) for each 5 yr. of age (Table 4, models 1, 2 respec tively). W hen chromium cumulative exposure was partitioned into three distinct latency intervals (5-9.99,10-19.99, 20 or more yrs), there was no improvement in fit, and the chromium exposure interaction with race remained.

# Estimates of Excess Lifetime Risk
Estimates of excess lifetime mortality from lung cancer resulting from up to 45 years of chromium exposure at concentrations 0.001-0.10 mg/m3 were calculated based on the preferred model with out the chromium-race interaction (Table 4, model 1). At 0.10 mg/m3 (the current OSHA standard for total hexavalent chromium as CrO3), 45 years of exposure corresponds to a cumulative expo sure of 4.5 mg/m3-yr and a predicted lifetime excess risk for lung cancer mortality of 255 per thou sand workers (95% CI: 109-416) (Table 5). At 0.01 mg/m3, one tenth of the current standard, 45 years of exposure corresponds to a lifetime excess risk of 31 per thousand workers (95% CI: 12-59). W hen the alternate log-linear model (Table 2, model 4.3) was used, the estimates of lifetime excess risk for lung cancer mortality were very similar (Table 5).

# DISCUSSION Model Choice
After consideration of a variety of log-linear and additive relative rate forms for modeling both smoking and chromium effects, a linear relative rate model with highly statistically significant ex posure effects was selected to describe the lung cancer-chromium exposure response and for cal culating excess lifetime risk. An equivalently fitting power model produced a slightly larger but less precise estimate of lifetime risk at the current PEL. The current findings are consistent with but not directly comparable to the results of Gibb et al. in the same population/ Gibb et al. used a log trans formation of cumulative exposure: ln(cumX+d), where d was the smallest measured background exposure in the study (d=1.4x10-6 mg/m3-yr). That metric was then used in a log-linear Cox regres sion model to estimate exposure-response.
Extensive and systematic historical environmental air-sampling data were available covering the entire period of employment for this study population. Over 70,000 measurements collected be tween 1950 and 1985 were available for the exposure assessment.1 These measurements were taken with the objective of characterizing typical rather than highest exposure scenarios, the latter being more commonly measured in industrial settings. The extent and quality of the exposure data are unique among chromium exposed populations and far exceed what is typically available for his torical cohort studies of occupational groups. Although the exposure information in this study has clear advantages over previous studies of chromium workers, it also has its limitations including a lack of information on particle size and also on variability of exposures of individual workers hav ing the same job title. Nonetheless, the measurement methodology used in the exposure surveys was generally consistent with what has been required by OSHA.

# Potential Confounding
Although asbestos was identified as a potential exposure in this cohort, we do not believe that it is likely to have been an important confounder in this investigation. As in most plants of this pe riod, asbestos was widely used and might have resulted in exposures among part of the workforce, particularly among skilled trades and maintenance workers (e.g., pipefitters, steamfitters, furnace or kiln repair and laborers). Asbestos exposure would not be expected to be generally correlated with chromium exposure in this population and thus should not have biased the internal exposureresponse analysis. Furthermore, no cases of mesothelioma were reported.
Although cigarette smoking was controlled for in this analysis, there is a possibility of residual confounding by smoking because of the crudeness of the smoking data which pertained only to the time of hire. However, this was considerably more smoking information than is usually found in occupational studies. Furthermore, for smoking to have been a strong confounder in this analysis, its intensity (packs per day) would have needed to vary by level of hexavalent chromium exposure concentration. O ur assumption that smokers started at 18 years of age and continued until the end of follow-up permitted the estimation of a time-dependent smoking cumulative exposure. A piece wise linear fitting of smoking cumulative exposure considerably improved model fit. It also indi cated that cumulative smoking greater than 30 pack-years, where smoking misclassification would be greater due to unknown lifetime smoking history, was not a significant predictor of further increased risk (Tables 2-4). Observing a plateau in the smoking cumulative exposure response was consistent with the pattern observed in previous studies of smoking.16 W hen smoking was modeled using the piece-wise linear terms, the parameter estimate of the chromium affect was increased by 10 percent, compared with use of the categorical specification for smoking.

# Exposure-Race Interaction
As indicated above, an exposure-race interaction was observed in our analyses. Because the source of this interaction is unknown, we chose not to include an interaction term in the final risk assess ment model. Discussion in the scientific literature of differential cancer rates and risks by race, focuses almost exclusively on socioeconomic, occupational and life-style risk factor differences Exposure Assessment and diagnostic bias. 17 We are not aware of examples establishing that occupational lung cancer susceptibility varies between African-Americans (majority of the nonwhite study population) and white Americans, and thus, in our opinion, it is unlikely that the chromium-race interaction that we observed has a biological basis. More plausible explanations include, but are not limited to: mis classification of smoking status, misclassification of chromium exposures, or chance. We have no evidence to support any of these explanations, however, and we believe that the exposure-response relationship derived for the entire study population provides the best basis for predicting risk.

# Excess Lifetime Risk and Prior Risk Assessments
Our analysis predicts, based on the preferred model (Table 4, Model 1), that workers exposed at the current OSHA PEL of 0.1 m g/m 3 for 45 years will have approximately 25% excess risk of dying from lung cancer due to their exposure. Very few workers in this study had cumulative exposures cor responding to 45 years at the PEL, and thus our estimates of risk are based on an upward extrapola tion from most of the data (less than 2% of person-years but 10% of lung cancer deaths occurred with cumulative exposures greater than 1.0 mg/m3-yr (Table 1)). However, even workers exposed at one tenth of the PEL (i.e., to 0.01 m g/m 3) would experience 3% excess deaths (Table 5).
There have been several other risk assessments for hexavalent chromium exposure and lung can cer, and it is informative to compare the predictions from these assessments with those from this investigation. In a 1995 review that included an earlier assessment of this cohort and the Mancuso study2, OSHA identified point estimates of lifetime risk at the current PEL (0.1 mg/m3) in the range of 88 to 342 per thousand.18 Conversion' of a U.S. Environmental Protection Agency risk as-sessment19 for ambient chromium exposures based on the Mancuso study, to predict occupational risks, produces estimated lifetime risks of 90 per thousand for 45 years of exposure to 0.1 mg/ m3. The State of California EPA published a risk assessment based on best estimates also from the Mancuso study with different assumptions about chromium exposures which, when converted for occupational exposures, result in a predicted lifetime occupational risk of 90 to 591 per thousand for exposure at the PEL.20 Thus the predicted occupational risks for lifetime exposure to the current OSHA PEL developed from these previous risk assessments, which ranged from 88 to 591 per 1000 workers, are quite consistent and bracket the estimate presented in this paper of 255 per 1000 work ers. Thus the estimates of risk for 45 years of exposure at the current OSHA PEL from previous risk assessments are all within a factor of 3 of the estimates provided in this paper, which is reasonably consistent given the uncertainties involved in the risk assessment process.

# CONCLUSION
This study clearly identifies a linear trend of increasing risk of lung cancer mortality with increasing cumulative exposure to water-soluble hexavalent chromium. O ur analysis predicts that exposure