1 NAC/Proposed 2: 11/2009

2

3

4

5 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

6 FOR 

MERCURY VAPOR (Hgo 7 )

8 (CAS Reg. No. 7439-97-6)

9

10 PROPOSED

11

12

13

14

15

16

17

18
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 2 of 51

1 PREFACE

2

3 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

7 chemicals.

8

9 AEGLs represent threshold exposure limits for the general public and are applicable to 

10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 

11 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 

12 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

13 The three AEGLs are defined as follows:

14

15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

cubic meter [ppm or mg/m3 16 ]) of a substance above which it is predicted that the general 

17 population, including susceptible individuals, could experience notable discomfort, irritation, or 

18 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 

19 transient and reversible upon cessation of exposure.

20

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3 21 ) of a substance above 

22 which it is predicted that the general population, including susceptible individuals, could 

23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

24 to escape.

25

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3 26 ) of a substance above 

27 which it is predicted that the general population, including susceptible individuals, could 

28 experience life-threatening health effects or death.

29

30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

31 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

32 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity 

34 of effects described for each corresponding AEGL. Although the AEGL values represent 

35 threshold levels for the general public, including susceptible subpopulations, such as infants, 

36 children, the elderly, persons with asthma, and those with other illnesses, it is recognized that 

37 individuals, subject to unique or idiosyncratic responses, could experience the effects described 

38 at concentrations below the corresponding AEGL.

39
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 3 of 51

1

2 TABLE OF CONTENTS

3 PREFACE.....................................................................................................................................................2

4 LIST OF TABLES ........................................................................................................................................5

5 EXECUTIVE SUMMARY...........................................................................................................................5

6 1. INTRODUCTION................................................................................................................................7

7 2. HUMAN TOXICITY DATA...............................................................................................................9

8 2.1. Acute Exposures..........................................................................................................................9

9 2.1.1. Lethality...................................................................................................................................9

10 2.1.2. Nonlethal Toxicity.................................................................................................................10

11 2.2. Occupational Monitoring ...........................................................................................................11

12 2.3. Neurotoxicity .............................................................................................................................11

13 2.4. Developmental/Reproductive Toxicity ......................................................................................11

14 2.5. Genotoxicity...............................................................................................................................12

15 2.6. Carcinogenicity..........................................................................................................................12

16 2.7. Summary....................................................................................................................................13

17 3. ANIMAL TOXICITY DATA ............................................................................................................13

18 3.1. Acute Studies.............................................................................................................................13

19 3.1.1. Rats........................................................................................................................................13

20 3.1.2. Mice.......................................................................................................................................14

21 3.1.3. Rabbits...................................................................................................................................14

22 3.2. Repeat-Dose Studies..................................................................................................................15

23 3.3. Neurotoxicity .............................................................................................................................17

24 3.4. Developmental/Reproductive Toxicity ......................................................................................18

25 3.5. Genotoxicity...............................................................................................................................22

26 3.6. Chronic Toxicity/Carcinogenicity..............................................................................................22

27 3.7. Summary....................................................................................................................................22

28 4. SPECIAL CONSIDERATIONS ........................................................................................................23

29 4.1. Metabolism and Disposition ......................................................................................................23

30 4.2. Mechanism of Toxicity ..............................................................................................................28

31 4.3. Structure-Activity Relationships................................................................................................28

32
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 4 of 51

1 4.4. Other Relevant Information .......................................................................................................28

2 4.4.1. Species Variability.................................................................................................................28

3 4.4.2. Susceptible Populations.........................................................................................................29

4 4.4.3. Concentration-Exposure Duration Relationship ....................................................................29

5 4.4.4. Concurrent Exposure Issues ..................................................................................................30

6 5. DATA ANALYSIS FOR AEGL-1.....................................................................................................30

7 5.1. Summary of Human Data Relevant to AEGL-1.........................................................................30

8 5.2. Summary of Animal Data Relevant to AEGL-1 ........................................................................30

9 5.3. Derivation of AEGL-1 Values...................................................................................................31

10 6. DATA ANALYSIS FOR AEGL-2.....................................................................................................31

11 6.1. Summary of Human Data Relevant to AEGL-2.........................................................................31

12 6.2. Summary of Animal Data Relevant to AEGL-2 ........................................................................31

13 6.3. Derivation of AEGL-2 Values...................................................................................................32

14 7. DATA ANALYSIS FOR AEGL-3.....................................................................................................33

15 7.1. Summary of Human Data Relevant to AEGL-3.........................................................................33

16 7.2. Summary of Animal Data Relevant to AEGL-3 ........................................................................33

17 7.3. Derivation of AEGL-3 Values...................................................................................................33

18 8. SUMMARY OF AEGLS ...................................................................................................................34

19 8.1. AEGL Values and Toxicity Endpoints ......................................................................................34

20 8.2. Comparison with Other Standards and Guidelines ....................................................................35

21 8.3. Data Adequacy and Research Needs..........................................................................................37

22 9. REFERENCES...................................................................................................................................37

23 APPENDIX A: Derivation of AEGL Values.............................................................................................45

24 APPENDIX B: Category Graph of AEGL Values and Toxicity Data........................................................48

25 APPENDIX C: Derivation Summary.........................................................................................................50

26
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 5 of 51

1 LIST OF TABLES

2

3 S 1. Summary of AEGL Values for Mercury Vapor .........................................................................................7

4 TABLE 1. Chemical and Physical Properties............................................................................................................8

TABLE 2. Estimated Human Exposures - Reconstructions of Accidental Exposuresa 5 ............................................10

6 TABLE 3. Summary of Acute Inhalation Data in Laboratory Animals ...................................................................15

7 TABLE 4. Summary of Repeat-Dose Inhalation Data in Laboratory Animals ........................................................16

8 TABLE 5. Reproductive, Developmental, and Developmental/Neurotoxicity Studies in Laboratory Animals.......19

9 TABLE 6. Human Metabolism Studies....................................................................................................................24

10 TABLE 7. Tissue Concentrations of Mercury .........................................................................................................26

11 TABLE 8. AEGL-1 Values for Mercury Vapor.......................................................................................................31

12 TABLE 9. AEGL-2 Values for Mercury Vapor.......................................................................................................33

13 TABLE 10. AEGL-3 Values for Mercury Vapor.......................................................................................................34

14 TABLE 11. Summary of AEGL Values for Mercury Vapor......................................................................................35

15 TABLE 12. Extant Standards and Guidelines for Mercury Vapor.............................................................................36

16
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 6 of 51

1 EXECUTIVE SUMMARY

2

Mercury vapor, Hg0 3 , (CAS Reg. No. 7439-97-6) is a colorless, odorless gas generated 

4 from elemental mercury or inorganic mercury compounds such as mercuric chloride. Under

5 ambient conditions, mercury is a silver-white, liquid metal. Metallic mercury is non-flammable 

6 and only slightly volatile (vapor pressure of 0.002 mm). 

7

8 Controlled inhalation studies in human volunteers that addressed metabolism used 

concentrations that ranged from 0.01 mg/m3 for 7 hours to 0.40 mg/m3 9 for 15 minutes. No 

10 complaints of ocular or respiratory tract irritation were reported in these studies. Review of past 

workplace exposure shows that concentrations of 0.4-2.0 mg/m3 11 in industry result in mercury 

poisoning only after chronic exposure. Concentrations of 1.0-5.0 mg/m3 12 were not unusual in 

13 mercury mining operations in the past (AIHA 2002). Additional human data were available from 

reconstructions of accidental exposures. An estimated airborne concentration of 16 mg/m3 14 for a 

few hours was lethal to an infant; whereas, an estimated concentration of 15 mg/m3 15 for 

16 0.75 hours failed to induce symptoms of Hg poisoning in high-school-age students. 

17

18 Animal studies addressed acute and repeat-dose toxicity, neurotoxicity, and 

19 developmental/reproductive toxicity. Death at high concentrations is due to damage to the lungs 

20 which results in respiratory failure. At lower concentrations, mercury vapor is neurotoxic. 

21 Absorbed mercury binds to various proteins, particularly thiol-containing proteins, resulting in 

22 nonspecific cell injury. Developmental studies that addressed neurotoxicity (primarily 

23 spontaneous activity and learning ability) yielded conflicting results. Sufficiently high mercury 

24 exposures can induce developmental toxicity at maternally toxic concentrations. Data were 

25 inadequate to determine the carcinogenic potential of mercury vapor. 

26

27 Mercury vapor has no odor. At low concentrations, there are no sensory or irritant 

28 warning properties. Therefore, AEGL-1 values are not recommended. 

29

30 Although maternal exposures were for 2 hours/day for 10 days, a single 2-hour exposure 

of pregnant Long-Evens rats to 4 mg/m3 31 mercury vapor (Morgan et al. 2002) was used as the 

32 point of departure for the AEGL-2. This value is a NOAEL for developmental effects. 

33 Developmental effects including increased resorption, decreased litter size and decreased 

neonatal weight were observed at the next higher concentration of 8 mg/m3 34 . Uncertainty factors 

35 for the AEGL-2 were based on a weight of evidence of approach. The following factors were 

considered in deriving an interspecies uncertainty factor: the 4 mg/m3 36 value was a NOAEL for 

37 developmental effects (below the definition of the AEGL-2), the exposures were repeated for 10 

38 days, rodents have a higher respiratory rate and cardiac output compared with humans (resulting 

39 in faster uptake), and human monitoring studies show some effects at concentrations of 0.4 to 2 

mg/m3 40 only with chronic exposure (AIHA 2002). The following factors were considered in 

41 ascribing an intraspecies uncertainty factor: the population of fetuses is considered a sensitive if 

42 not the most sensitive population, the protective action of the placenta in sequestering mercury 

[the mean concentration of mercury in the brain of dams exposed to 4 mg/m3 43 for 10 days was 60-

44 fold higher than in the fetal brain (Morgan et al. 2002)], and incidences of miscarriages and 

45 stillbirths were unaffected in women chronically exposed to mercury vapor (median air 

concentration, 0.09 mg/m3

; range, 0.025-0.60 mg/m3 46 ), although congenital anomalies were 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 7 of 51

1 statistically non-significantly increased (Elghany et al. 1997). Based on these factors, 

2 interspecies and intraspecies uncertainty factors of 1 and 3 were applied. Application of larger 

uncertainty factors, for example 10 or 30 (resulting in 2-hour values of 0.4 or 0.13 mg/m3 3 ), 

4 results in values that are inconsistent with the available human data, including the chronic 

5 exposure of pregnant women in the study of Elghany et al. (1997). In the absence of time-scaling 

information, the resulting 2-hour value of 1.33 mg/m3 6 was time-scaled using default n values of 3 

7 and 1 for shorter and longer exposure durations, respectively (NRC 2001). 

8

9 The AEGL-3 values were based on a single 1-hour exposure of male Wistar rats to 26.7 

mg/m3 10 ; no deaths occurred during the 15-day post-exposure period (Livardjani et al. 1991). No 

11 clinical signs were observed, but lungs showed edema and necrosis. Extending the exposure 

12 period for another hour (at approximately the same concentration) resulted in 62.5% mortality. 

This 1-hour highest non-lethal value of 26.7 mg/m3 13 meets the definition of the AEGL-3. The 

26.7 mg/m3 14 value was adjusted by a total uncertainty factor of 3 (an interspecies uncertainty 

15 factor of 1 and an intraspecies uncertainty factor of 3) based on a weight of evidence approach. 

16 Larger uncertainty factors result in values incompatible with the overall data. Reversible 

behavioral changes were observed in male and female Wistar rats inhaling 17.2 mg/m3 17 for 2 

18 hours/day for 22 exposures (Beliles et al. 1968). The uncertainty factor of 3 is considered 

19 sufficient to protect susceptible populations. Values derived using an intraspecies uncertainty 

20 factor of 3 are supported by the non-lethal concentrations estimated in accidental exposures [up 

to 15 mg/m3 21 for 0.75 hours [Shelnitz et al. 1988; AIHA 2002)] and measured in occupational 

settings [0.4-2.0 mg/m3 (AIHA 2002)]. The resulting 1-hour value of 8.9 mg/m3 22 was time-scaled 

23 using default n values of 3 and 1 for shorter and longer exposure durations, respectively (NRC 

2001). Because the 8-hour time-scaled value of 1.1 mg/m3 24 appears low in comparison to 

25 accidental non-lethal exposures and is lower than some chronic occupational exposures, the 8-

26 hour value was set equal to the 4-hour value.

27

28 The calculated values are listed in the table below. 

29

S 1. Summary of AEGL Values for Mercury Vapor

Classification 10-min 30-min 1-h 4-h 8-h Endpoint (Reference)

AEGLB1a

(Nondisabling)

Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended

No odor or warning 

properties

AEGLB2

(Disabling)

3.1 mg/m3

(0.38 ppm)

2.1 mg/m3

(0.26 ppm)

1.7 mg/m3

(0.21 ppm)

0.67 mg/m3

(0.08 ppm)

0.33 mg/m3

(0.04 ppm)

No fetal effects: 

4 mg/m3, 2 hours/day, 

10 d – rat 

(Morgan et al. 2002)

AEGLB3

(Lethal)

16 mg/m3

(2.0 ppm)

11 mg/m3

(1.3 ppm)

8.9 mg/m3

(1.1 ppm)

2.2 mg/m3

(0.27 ppm)

2.2 mg/m3

(0.27 ppm)

Highest non-lethal 

value, 26.7 mg/m3 for 

1 h - rat 

(Livardjani et al. 1991)

a 30 Mercury vapor is odorless. AEGL-1 values are not recommended because mercury vapor has no odor or warning 

31 properties at concentrations that may cause health effects.

32

33 1. INTRODUCTION

34

35 Mercury vapor (CAS Reg. No. 7439-97-6) is a colorless and odorless gas generated from 

36 elemental mercury or inorganic mercury compounds. The metallic form of mercury and the 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 8 of 51

vapor exist in the zero oxidation state (Hgo 1 ). At ambient conditions, mercury is a silver-white, 

2 liquid metal. It is non-flammable and only slightly volatile (vapor pressure of 0.002 mm). 

3 Mercury is practically insoluble in water, but is soluble in many organic solvents (O=Neil et al. 

4 2001; AIHA 2002). Additional chemical and physical properties are summarized in Table 1. 

5

6 Due to its unique chemical and physical properties such as uniform volume expansion 

7 over its entire liquid range, mercury has many uses. It is used in the chloralkali industry as a 

8 cathode in the electrolysis of brine and in making a variety of scientific instruments and electrical 

9 control devices, as an amalgam tooth filling, and in mining for the extraction of gold (Goyer and 

10 Clarkson 2001). Dental amalgam contains 50% mercury. In the past, liquid elemental mercury 

11 was a common component of thermometers, barometers, and other laboratory measuring devices. 

12 The largest commercial use of mercury in the U.S. (35%) is for electrolytic production of 

13 chlorine and caustic soda in mercury cells. In 1995, U.S. consumption was 463 metric tons 

14 (ATSDR 1999). The use of mercury in batteries, pigments, explosives, and as a catalyst for 

15 production of various plastics has been discontinued in the U.S. (U.S. EPA 1992).

16

17 Mercury is a naturally occurring element in the earth=s crust. Mercury is mined from 

18 cinnebar ore. World wide, cinnebar is mined by open-pit and underground mining; cinnebar is 

19 no longer mined in the U.S. The primary method of mercury extraction from ore is by heating in 

20 a retort or furnace. Leaching, electrolysis, and electro-oxidation methods have also been used. 

21 Primary mercury production has decreased due to mercury recovery and recycling. Use has also 

22 declined due to legal restrictions; in the U.S., mercurial compounds are no longer used as 

23 biocides in protective coatings and in seed treatment. In 2003, world mine production from the 

24 four major producing countries was 1300-1400 tons (DeVito and Brooks, 2005). 

25

TABLE 1. Chemical and Physical Properties

Parameter Value Reference

Synonyms Metallic mercury vapor; 

elemental mercury vapor;

quicksilver (solid form)

AIHA 2002

Chemical formula Hg O=Neil et al. 2001

Molecular weight 200.59 O=Neil et al. 2001

CAS Reg. No. 7439-97-6 AIHA 2002

Physical state Liquid metal; colorless vapor 

generated from elemental liquid 

mercury or inorganic compounds of 

mercury

AIHA 2002

Solubility in water 0.28 moles/L (insoluble) O=Neil et al. 2001

Vapor pressure (25C) 2 x 10-3 (mm Hg) O=Neil et al. 2001

Vapor density (air =1) 6.9 AIHA 2002

Saturation concentration in air 13 mg/m3 (1.6 ppm) at 20C

16 mg/m3 (2.0 ppm) at 22C

30 mg/m3 3.7 ppm at 30C

111 mg/m3 (13.5 ppm) at 50C

AIHA 2002

Liquid density (water =1) 13.5 g/cm3 at 25C O=Neil et al. 2001

Melting point -38.9C O=Neil et al. 2001

Boiling point 356.7C O=Neil et al. 2001

Flammability limits Not flammable AIHA 2002
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 9 of 51

Conversion factors* 1 ppm = 8.20 mg/m3

1 mg/m3 = 0.122 ppm

AIHA 2002

*In this document, values reported in ppm have been converted to mg/m3 1 for consistency.

2

3 2. HUMAN TOXICITY DATA

4

5 Mercury vapor is odorless (ATSDR 1999).

6

7 Mercury vapor emitted from amalgam dental fillings is the major source of mercury 

8 exposure of the general public. Mercury excretion correlates with the number of “faces” of the 

9 amalgam fillings. Other sources of mercury include natural degassing of the earth=s crust, food, 

10 and occupational exposure. Diet represents about 1.66 nmol/day compared with fillings, 

11 15-85 nmol/day. Quantities emitted from the earth=s surface are believed to be equal to those 

12 from industrial applications (WHO 2003; Goyer and Clarkson 2001).

13

14 Exposure of humans to extremely high concentrations of mercury vapor may produce an 

15 acute, corrosive bronchitis and interstitial pneumonitis (Goyer and Clarkson 2001). At sublethal 

16 concentrations, symptoms include tremor or increased excitability. Chronic exposure can result 

17 in a variety of neuromotor effects including tremor, ataxia, weakness and erethism, characterized 

18 by withdrawal, depression, sensory and sleep disturbances, and emotional lability (Newland et al. 

19 1996). Increased excitability, tremors, and gingivitis have been associated historically with 

20 inhalation of mercury vapor and exposure to mercury nitrate in the fur, felt, and hat industries. 

21 Acrodynia (pink disease) has been reported in infants exposed via contaminated clothes and 

22 carpeting (ACGIH 1996). Mercury was once a common additive in teething powders and other 

23 baby products, and sensitive infants developed skin rash.

24

25 Studies on the toxicity of mercury vapor have been reviewed by Friberg and Vostal 

26 (1972), U.S. EPA (1995), ACGIH (1996), ATSDR (1999), AIHA (2002), and WHO (2003).

27

28 2.1. Acute Exposures

29 2.1.1. Lethality 

30

31 Concentrations lethal to humans have been reconstructed from accidental exposures 

32 (Table 2). These accidents resulted from heating of metallic mercury. Death in all cases was 

33 attributed to respiratory failure. Three reports that included fatalities were summarized by AIHA 

34 (2002) as follows. Eight employees were accidentally exposed during recovery of tons of warm 

35 mercury spilled from a ruptured generator (Tennant et al. 1961). The exposure duration was 3-5 

hours and the atmospheric concentrations were estimated at 18-30 mg/m3 36 (2.2-3.7 ppm) based on 

37 mercury in autopsy samples as well as the concentration of mercury in saturated air in a warm 

38 room. All eight employees became ill, and one died. In the second report, torches were used in a 

39 confined space to cut mercury-contaminated pipes (Eto et al. 1999; Kurisaki et al. 1999; Asano et 

40 al. 2000). All 27 employees became ill and three died. The duration of exposure was 2-3 hours 

for the three fatalities and the concentration was estimated at 43 mg/m3 41 (5.2 ppm) based on a 

42 simulation of the accident. The simulation was consistent with mercury found in autopsy tissues. 

43 In one other case, liquid mercury was accidentally spilled on a hot stove. All three exposed 

44 individuals became ill; the only fatality was an infant (Campbell 1948). According to the study 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 10 of 51

1 author, different medical intervention would have been applied if the exposure to mercury had 

2 been reported when the infant was admitted to hospital. 

3

4 2.1.2. Nonlethal Toxicity 

5

6 Data on acute exposures are available only from reconstruction of accidents and 

7 metabolism studies (See Section 4.1 for metabolism studies). AIHA (2002) described two 

instances in which exposures to estimated concentrations of 13 mg/m3 8 (1.6 ppm) for 3-5 hours or

16 mg/m3 9 (2 ppm) for <8 hours produced cough, dyspnea, and chest tightness (Seaton and 

10 Bishop 1978; McFarland and Reigel 1978). In a third report, high-school-age students exposed 

to an estimated 15 mg/m3 (1.8 ppm) for 0.75 hours failed to exhibit signs of acute Hg0 11 poisoning

12 (Shelnitz et al. 1988). Exposure of the students was verified by long-term measurements of 

13 urinary mercury. Two additional reports of gold ore processing in a home resulted in illness, but 

no fatalities. The estimated concentration was 16 mg/m3 14 and the duration was estimated at a few 

15 hours.

16

TABLE 2. Estimated Human Exposures - Reconstructions of Accidental Exposuresa

Exposure Situation

(Reference)

Estimated 

Exposure Time Estimated Concentration

Number Exposed

(Number ill,b fatalities)

Recovery of tons of mercury 

from ruptured generator

(Tennant et al. 1961)

3-5 h 18-30 mg/m3 (2.2-3.7 ppm) 8 (8, 1)

Torches used in confined space 

to cut contaminated pipes (Eto 

et al. 1999; Kurisaki et al. 

1999; Asano et al. 2000))

2-3 h 43 mg/m3 (5.2 ppm)c 27 (27, 3)

Liquid mercury poured on 

stoved (Campbell 1948)

“few h” 16 mg/m3 (2 ppm) 3 (3, 1 [infant])

Home gold ore processingd

(Haddad and Stenberg 1963)

“few h” 16 mg/m3 (2 ppm) 2 (2, 0)

Home gold ore processingd

(Hallee 1969)

“few h” 16 mg/m3 (2 ppm) 5 (5, 0)

Workers exposed to vaporized 

mercury in airflowe (Seaton and 

Bishop 1978)

3-5 h 13 mg/m3 (1.6 ppm) 4 (4, 0)

Broken thermostat on hot oven 

in small building (McFarland 

and Reigel 1978)

<8 h 44.3 mg/m3 (5.4 ppm)c 9 (6, 0)

Mercuric oxide heated in 

unventilated school laboratoryd

(Shelnitz et al. 1988)

0.75 h 15 mg/m3 (1.8 ppm) 23 (0, 0)

a 17 Data taken from AIHA 2002. b 18 Symptoms summarized in text. c AIHA (2002) reported an estimated concentration of 16 mg/m3 19 (see footnote d). d 20 The minimum of the computed air concentration (mass of vaporized mercury divided by volume of enclosed area) 

and the theoretical air saturation concentration for mercury vapor (16 mg/m3 21 ) at the known or assumed air 

22 temperature of 22oC.

e Mercury vaporized (estimated at 100 mL) at 90oC, blown into a pressure chamber at 500 ft3 23 /min, temperature of 

walls 260 oC, then into chamber (7.2 x 2.4 x 1.8 m) containing workers at 20oC. Twenty hours later, 2 mg/m3 24

25 measured by Drager tube.
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 11 of 51

1

2 Milne et al (1970) reported that four workmen became ill for up to a month after exposure 

3 to mercury while repairing a mercury-contaminated tank. Individual exposures depended on task 

4 performed, and ranged from 2.5 to 5 hours. A simulation of the accident while repairing a 

similar tank showed mercury concentrations of 1.1 to 2.9 mg/m3 5 in the breathing zone of the 

6 workmen. During the actual exposure, a nearby small steam heating pipe was inadvertently left 

7 turned on, likely increasing the mercury concentrations in the tank.

8

9 2.2. Occupational Monitoring

10

11 Personal sampling of two workers during maintenance operations at a chloralkali plant 

showed TWAs of metallic mercury vapor of 0.152 mg/m3 (0.019 ppm) and 0.131 mg/m3 12

13 (0.016 ppm) (Barregard et al. 1992). Total exposure times were 20 and 23 hours, respectively, 

14 over two days. On the third day both subjects were exposed to an average concentration of 

0.190 mg/m3 15 (0.023 ppm) for 8 hours. Stationary sampling in the room showed a TWA of 

0.060 mg/m3 16 (0.007 ppm). For an additional 7 workers, concentrations in work rooms were 

between 0.010 and 0.400 mg/m3 17 (0.001 and 0.049 ppm). Two of the workers (not clearly stated 

18 which ones) had used respiratory equipment during 15% of the working hours. Symptoms were 

19 not addressed, but maintenance operations appeared to be routine. 

20

21 IARC (1993) summarized occupational exposure to mercury in various industries and 

occupations. Mean air concentrations ranged up to 0.20 mg/m3 22 (0.024 ppm). IARC pointed out 

23 that these general air samples are usually lower than personal samples. Biological monitoring 

24 (blood and urine samples) reflected the exposure concentrations. A review of occupational 

25 monitoring studies by WHO (2003) suggests that an increased prevalence of subclinical 

26 symptoms such as slight objective changes in short-term memory or tremor may occur with longterm exposure to mercury vapor at levels 20 g/m3 27 (0.0024 ppm). 

28

29 AIHA (2002) summarized past workplace exposures. Concentrations in the range of 

0.4-2 mg/m3 30 (0.05-0.25 ppm) in industries have resulted in chronic mercury poisoning. Air 

concentrations of 1.0-5.0 mg/m3 31 (0.12-0.61 ppm) were not unusual in mercury mining operations 

32 in the past.

33

34 2.3. Neurotoxicity

35

36 Effects of mercury vapor on the central nervous system have been well documented 

37 (Goyer and Clarkson 2001). As noted, high, acute, non-fatal concentrations produce tremor and 

38 increased excitability and can induce pneumonitis. At lower concentrations, symptoms may be 

39 non-specific. Specific concentrations at which these symptoms occur were not provided.

40

41 2.4. Developmental/Reproductive Toxicity

42

43 Studies addressing the effect of mercury vapor on human reproduction and development 

44 were summarized by ACGIH (1996), ATSDR (1999), and AIHA (2002). No numeric acute45 duration exposure data were available. Retrospective studies on human fertility were evenly 

46 divided between those showing an effect and those showing no effect. Developmental data were 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 12 of 51

1 similarly inconclusive. Exposure concentrations were not provided in most studies. A 28-year 

2 study of pregnancies in 57 women chronically exposed to inorganic mercury vapor (median air 

concentration, 0.09 mg/m3; range, 0.025-0.60 mg/m3 3 ) did not reveal a significant difference from 

4 27 controls regarding miscarriages or stillbirths (Elghany et al. 1997). The overall fetal death 

5 rate was similar to that of New York state and national levels for the same period. Although 

6 statistically non-significant, the incidence of congenital anomalies including clubfoot and 

7 extrophy of the bladder was higher in Hg-exposed workers than in unexposed workers (4.2% vs 

8 0%). But, there was no apparent concentration-response relationship for the congenital 

anomalies (concentrations of 0.025 to 0.23 mg/m3 9 ); however, the study authors noted the small 

10 size of their study population and suggested that additional studies, either a larger, retrospective 

11 or prospective epidemiological study, be conducted. Health habits of the pregnant women were 

12 not assessed. Inorganic mercury concentrations were monitored using a portable, ultraviolet 

13 absorption mercury vapor meter. Samples were taken in the area of the workers faces. 

14

15 According to AIHA (2002), case studies of accidental exposures suggest that infants and 

16 toddlers are at greater risk than older children and adults of developing severe and progressive 

17 lung injury. Many of these studies did not cite concentrations. In some cases, infants may have 

18 experienced higher exposure while crawling on the floor. Campbell (1948) reports that an infant 

19 that died from mercury poisoning was close to a hot stove on which mercury was vaporized. 

20 Symptoms of fatigue, nausea, and abdominal cramps were reported in two adults in the 

21 household.

22

23 The concentration of total mercury in brain and kidney of 18-19 terminated fetuses and 

24 14-15 deceased infants was analyzed by Lutz et al. (1996). The mean concentrations of mercury 

25 in the brain of fetuses and infants were 5 and 6 μg/kg (ng/g) wet weight (range, ≤2-23 μg/kg). 

26 The mean concentrations in the kidney of fetuses and infants were 9 μg/kg (range, ≤5-34 μg/kg) 

27 and 12 μg/kg (range, 3-37 μg/kg), respectively (data summarized in Table 7). There was a 

28 tendency of increasing concentration of mercury in the fetal kidney but not in the brain with 

29 increasing number of amalgam fillings in the mothers. The mercury in the tissue samples was 

30 not speciated, and, based on results of other studies, the authors indicate that most of the mercury 

31 in the brain may be methyl mercury. These mean values for mercury in the human brain are 

similar to that found by Fredriksson et al. (1996) for rats exposed in utero to 1.8 mg/m3 32 during 

33 PND 2-3.

34

35 2.5. Genotoxicity

36

37 Evidence for the genotoxicity of mercury vapor is limited. Cytogenetic monitoring 

38 studies of occupationally-exposed workers produced mixed results, but the overall findings in 

39 studies with appropriate control groups found no convincing evidence that mercury adversely 

40 affects the number or structure of chromosomes in human somatic cells (ATSDR 1999; U.S. 

41 EPA 1995).

42

43 2.6. Carcinogenicity

44

45 Chronic toxicity/carcinogenicity studies were summarized by ACGIH (1996) and the U.S. 

46 EPA (1995). ACGIH used an A4 classification - not classifiable as a human carcinogen - for 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 13 of 51

1 inorganic forms of mercury including metallic mercury. The U.S. EPA in their Integrated Risk 

2 Information System (IRIS) considered the evidence for both animal and human carcinogenicity 

3 inadequate and assigned a classification of D - not classifiable as to human carcinogenicity. The 

U.S. EPA identified a LOAEL for systemic effects of 0.025 mg/m3 4 (0.003 ppm) for chronic 

5 (8-hours/day) exposures. The critical effects were hand tremor, increases in memory disturbance, 

6 and slight subjective and objective evidence of autonomic dysfunction. A NOAEL was not 

7 identified.

8

9 2.7. Summary

10

11 Data on human exposure to mercury vapor are limited to accidental exposures and 

12 occupational monitoring. Concentrations from the reconstructed accidental exposures were 

13 based on symptoms, estimated releases, room size, urinary mercury excretion, and, in cases of 

death, tissue concentrations at autopsy. Estimated exposures of 3-5 hours to 18-30 mg/m3 14 (2.2-

3.7 ppm) and 2-3 hours at 43 mg/m3 15 (5.2 ppm) killed some workers (AIHA 2002). Exposures to 

concentrations of 13-16 mg/m3 16 (1.6-2 ppm) for several hours caused cough, shortness of breath, 

17 and chest tightness (Seaton and Bishop 1978; McFarland and Reigel 1978; AIHA 2002). One 

case report of exposure to 15 mg/m3 18 (1.8 ppm) for 0.75 hours found no overt symptoms (Shelnitz 

et al. 1988). An estimated concentration of 16 mg/m3 19 was not lethal to adults, but one infant died 

20 following exposure of a “few hours.”

21

22 Occupational studies indicate that exposure to mercury vapor concentrations of 0.4-

2 mg/m3 23 (0.05-0.25 ppm) may induce symptoms of mercury intoxication but only after repeated 

24 exposure over several weeks or longer. Signs of Hg poisoning have not been reported for 

25 exposure to these concentrations for hours or days (AIHA 2002).

26

27 Human developmental studies indicate a potential for an increase in fetal anomalies as a 

28 result of mercury vapor exposure, but the limited studies to date have not shown a statistically 

29 significant relationship. Additionally, the American Industrial Hygiene Association reported that 

30 the young child may be at greater risk for developing severe and progressive lung injury (AIHA 

31 2002). Mercury vapor does not appear to be genotoxic. Studies are too limited to allow a 

32 conclusion concerning its carcinogenic potential.

33

34 3. ANIMAL TOXICITY DATA

35 3.1. Acute Studies

36

37 Acute studies with both lethal and non-lethal endpoints are summarized in Table 3. 

38

39 3.1.1. Rats

40

41 Groups of 32 male Wistar rats inhaled (whole-body) analytically-determined 

concentrations of 26.7 mg/m3 (3.25 ppm) for one hour or 27.0 mg/m3 42 (3.29 ppm) for two hours 

43 (Livardjani et al. 1991). Sacrifices took place from 1 to 15 days postexposure. No rats exposed 

to 26.7 mg/m3 44 for one hour died and no clinical signs were evident. Animals inhaling 27.0 

mg/m3 45 for two hours showed dyspnea and 20 died within 5 days of exposure. Microscopic 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 14 of 51

1 examination of the lung tissue revealed alveolar edema, hyaline membranes, and occasional 

2 fibrosis. 

3

4 3.1.2. Mice

5

Groups of 16 C57Bl6 wild-type and metallothionein-null mice inhaled 0 or 5.5-6.7 mg/m3 6

7 (0.67-0.82 ppm) of mercury vapor for 3 hours, and the mice were killed at 1, 24, 72, or 168 hours 

8 post-exposure (Yoshida et al. 1999a). Metallothionein was induced in the lungs, kidneys, and 

9 brain. Liver and kidney function, as determined by glutamate oxaloacetate transaminase and 

10 glutamate pyruvate transaminase activity, blood urea nitrogen, and serum creatinine, were all 

11 within normal limits.

12

13 Twenty-four male ICR mice inhaled an analytically-determined concentration of 9.8 

mg/m3 14 (1.2 ppm) mercury vapor for 1 hour; groups of six animals were sacrificed at 1, 24, 48, 

15 and 120 hours after exposure (Shimojo et al. 1996). Protein in broncho-alveolar lavage fluid 

16 (BALF) was used as a marker of lung injury. Protein in BALF increased with time: 169% of the 

17 control value at both 1 and 24 hours and 441% of the control value at 48 hours. At 48 hours after 

18 exposure, BALF contained large amounts of hemoglobin, indicating pulmonary hemorrhage. 

19 Superoxide dismutase, an antioxidant enzyme, increased following exposure, but returned to a 

20 near control level by 120 hours postexposure. Mortality was not addressed.

21

22 3.1.3. Rabbits

23

24 Rabbits were exposed to mercury vapor at an average analytically-determined 

concentration of 28.7 mg/m3 25 (3.5 ppm) for 1 to 30 hours (Ashe et al. 1953). Fourteen rabbits 

26 were used, with one or two at each exposure duration. The longer exposure durations were 

27 conducted intermittently, over periods of several days. Surviving animals were sacrificed on the 

6th 28 day after exposure ended. Two rabbits exposed for one hour showed mild to moderate 

29 damage to the brain, kidney, heart, and lung (not further described). A two-hour exposure (2 

30 rabbits) resulted in marked cellular degeneration of the kidney and brain. Exposure for 4 hours 

31 resulted in moderate to marked cellular degeneration of the heart, liver, and lungs and severe 

32 damage to the kidney and brain. Severe damage was characterized as nearly complete 

destruction with widespread necrosis. One rabbit inhaling Hg0 33 for 6 hours/day for 5 days (total 

34 of 30 hours) died near the end of exposure.

35
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 15 of 51

TABLE 3. Summary of Acute Inhalation Data in Laboratory Animals

Species

Concentration

(ppm)

Exposure 

Time Effect Reference

Rat 26.7 mg/m3

(3.25)

27.0 mg/m3

(3.29)

1 h

2 h

No deaths; mild lung lesions; 

no breathing difficulties

Death of 20/32; severe lung 

lesions; dyspnea 

Livardjani et al. 1991

Mouse 5.5-6.7 mg/m3

(0.67-0.82)

3 h Normal liver and kidney 

function

Yoshida et al. 1999a

Mouse 9.8 mg/m3

(1.2)

1 h Increased protein content of 

broncho-alveolar lavage fluid

Shimojo et al. 1996

Rabbit 28.7 mg/m3

(3.5)

1 h

4 h

Mild organ damage

severe organ damage

Ashe et al. 1953

1

2 3.2. Repeat-Dose Studies

3

4 Recent repeat-dose studies are summarized in Table 4. Older studies are described in the 

5 following text, but, because of design flaws and outdated analytical methodology, are not 

6 included in Table 4. Data from repeat-exposure studies that addressed neurotoxicity are 

7 summarized in Table 4, but are discussed in Section 3.3. Studies in Table 4 are arranged first by 

8 species and then by increasing concentration. Data from repeat-exposure studies that addressed 

9 pregnancy outcome are included in Table 5 and are discussed in Section 3.4.

10

Two dogs exposed 8 hours/day for 40 days to 1.89 mg/m3 11 (0.23 ppm) showed no clinical 

signs (Fraser et al. 1934). Six dogs exposed 8 hours/day to 15.29 to 20.06 mg/m3 12 (1.86-2.44

ppm) died within 1-3 days and two of six dogs exposed daily for 8 hours to 12.55 mg/m3 13 (1.53

14 ppm) died within 2-3 days. The remaining dogs developed shortness of breath, weakness, 

15 vomiting, and diarrhea. Although well-conducted for the time, this study suffers from outdated 

16 analytical methodology and the reported exposure concentrations are not reliable.

17

Groups of 25 female Long-Evans rats were exposed nose-only to 4 mg/m3 18 (0.49 ppm) 2 

19 hours/day for up to 10 days (Brambila et al. 2002). Groups of 5 treated and 5 control rats were 

20 sacrificed on days 1, 5, 10, 17, and 37. Microscopic examination of kidneys failed to reveal 

21 tissue damage in the kidney (the only organ examined). No clinical effects were described and 

22 no deaths were mentioned at sacrifice on day 37.

23

24 No clinical signs other than slight body weight loss (data not provided) were observed in 

25 male and female brown Norway rats (groups of 7) exposed to a measured concentration of 1 

mg/m3 26 (0.12 ppm) of mercury vapor for 24 hours/day, 7 days/week, for 5 weeks or 6 hours/day, 

27 3 days/week for 5 weeks (Warfvinge et al. 1992). One rat in the continuous exposure group died 

28 of kidney damage after 4 weeks of exposure. Neurological examinations were not performed. 

29 The mercury exposure induced an autoimmune disease (not otherwise described) (Hua et al. 

30 1992). 

31

No deaths occurred in a group of female Wistar rats exposed to 1 mg/m3 32 (0.12 ppm), 24 

33 hours/day for 28 days (Gage 1961). After 10 days of continuous exposure, a steady-state was 

34 achieved in that elimination of mercury in the urine was equal to absorption.
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 16 of 51

1

TABLE 4. Summary of Repeat-Dose Inhalation Data in Laboratory Animals

Species

Concentration 

(ppm)

Exposure 

Duration Effect Reference

Rat, male 

Wistar

0.48 mg/m3 (0.06) 5 h/d, 4-5 d/wk, 

8 wk

“Irritable” behavior during 

weeks 6-8; microscopic 

changes in nervous system

Schionning et al. 1998; 

Sorensen et al. 2000

Rat, 

Norway

1 mg/m3

(0.12)

24 h/d,

7 d/wk,

5 wks

One death (of 7 rats) after 5 

weeks of exposure 

Warfvinge et al. 1992

Rat, female, 

Wistar

1 mg/m3

(0.12)

24 h/d,

28 d

All rats survived; weight 

loss; lethargy by the 7th day; 

slight tremors when handled 

at termination

Gage 1961

Rat, male, 

(strain 

unidentified)

3.0 mg/m3 (0.37) 3 h/d, 5 d/wk, 

12-42 weeks

Reversible tremors at 18 

weeks; except for kidney 

changes, normal 

histopathology at sacrifice

Kishi et al. 1978

Rat, female, 

Long-Evans

4 mg/m3

(0.49)

2 h/d,

10 d

No deaths, no kidney 

damage

Brambila et al. 2000

Rat, male and 

female Wistar

17.2 mg/m3 2 h/d, 5 d/wk, 

30 days

Reversible behavioral 

changes (increase in escape 

response and response time 

latency at 15 days; decrease 

in avoidance response

Beliles et al. 1968

Mouse, 

C57Bl6

0.06 mg/m3

(0.007)

8 h/d,

23 wk

Neurobehavioral effects 

(increased activity) 

Yoshida et al. 2004

Mouse,

C57Bl6

0.1 mg/m3

(0.12)

4.1 mg/m3

(0.50)

1 h/d, 3 d/wk, 

two wk, 

followed by 30 

min/d, 3 d/w,

11 wk

No toxic signs and no deaths Yasutake et al. 2004

Mouse,

C57Bl6

6.6-7.5 mg/m3

(0.80-0.91)

4 h/d,

3 d

No deaths, no lung lesions Yoshida et al. 1999b

Rabbit, male 4.0 mg/m3 (0.49) 6 h/d, 4 d/wk, 

13 wk

Slight tremors and clonus at 

13 weeks

Fukuda 1971

2

3

4 No deaths occurred and no signs of toxicity were evident in wild-type or metallothioneinnull mice exposed to 0.1 mg/m3 5 (0.1 ppm) for 1 hour/day, 3 days/week for two weeks, followed 

by exposure to 4.1 mg/m3 6 for 30 minutes/day, 3 days/week for 11 weeks (Yasutake et al. 2004). 

7 Metallothionein was induced/increased in the brains of wild-type mice. Mercury could be 

8 detected histochemically in the brains of both strains of mice, but no pathological change was 

9 observed. When tested at 12 and 23 weeks, increased activity and decreased passive avoidance 

were observed in female OLA129/C57BL6 mice following exposure to 0.06 mg/m3 10 for 8 

11 hours/day for 23 weeks (Yoshida et al. 2004). These effects were greater in metallothionein-null

12 mice. 

13

Groups of 14 C57Bl6 wild-type and metallothionein-null mice inhaled 0 or 6.6-7.5 mg/m3 14

15 of mercury vapor for 4 hours/day for 3 consecutive days (Yoshida et al. 1999b). Seven mice 

16 from each group were sacrificed 24 hours after the first exposure. Clinical signs were not 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 17 of 51

1 described. No wild-type mice died over the 3-day period. Two and eight metallothionein-null 

2 mice died within 24 hours after 2 and 3 days of exposure, respectively. Pulmonary histology 

3 showed congestion, atelectasis, and mild to moderate hemorrhage in the alveoli of both wild-type 

4 and metallothionein-null mice. The lesions were more severe in the metallothionein-null mice 

5 and, for both groups, became more pronounced as exposure duration increased. With increasing 

6 exposure duration, metallothionein increased in the lungs of wild-type mice, but not in the lungs 

7 of metallothionein-null mice.

8

A group of 16 rabbits inhaled 6.0 mg/m3 9 (0.73 ppm) mercury vapor for 7 hours/day, 5 

10 days/week (Ashe et al. 1953). Exposures continued for up to 12 weeks. None of the rabbits 

11 died. A rabbit exposed for one week showed mild to moderate damage of the kidney, liver, 

12 brain, heart, and lung. In most cases, damage to the kidney and brain became more severe with 

13 longer exposures and was described as ranging from marked cellular degeneration with some 

14 necrosis to nearly complete destruction with widespread necrosis. 

15

16 3.3. Neurotoxicity

17

18 Neurotoxicity studies are discussed below. Developmental neurotoxicity studies are 

19 summarized in Section 3.4 and Table 5.

20

Adult male Wistar rats inhaled 0.48 mg/m3 21 of metallic mercury for 5 hours/day, 4 or 5 

22 days/week over an 8-week period (Schionning et al. 1998; Sorensen et al. 2000). During the last 

23 2-3 weeks of exposure, the treated rats became “irritable” and food and water intake were 

24 decreased. Analysis of changes in the nerve tissue was by microscopic “stereological” 

25 observations. The peripheral nervous system was little affected. The mean cross section of 

26 myelin associated with nerve fibers in the dorsal nerve roots was significantly reduced (by 20%) 

27 and there was a tendency towards a reduction in axon area of myelinated nerve fibers in the 

28 dorsal nerve roots and in the total numbers and mean volume of some cell types. The central 

29 nervous system (cerebellum) showed reductions in numbers of Purkinje and granule cells and 

30 volume of the granular cell layer.

31

32 Reversible behavioral changes were observed in male and female Wistar-derived rats 

exposed to 17.2 mg/m3 33 (2.1 ppm) mercury vapor for 2 hours/day, 5 days/week for 18-22 

exposures over 30 days (Beliles et al. 1968) and 14 male Wistar rats exposed to 3.0 mg/m3 34 (0.37 

35 ppm) mercury vapor for 3 hours/day, 5 days/week for 12 to 42 weeks (Kishi et al. 1978). In the 

36 first study, six female albino rats were used in avoidance escape studies (five controls) and seven

37 pairs of male rats were used in reflexive fighting studies (five control pairs). Mercury exposure 

38 produced an increase in escape response latency and a decrease in avoidance responding when 

39 tested during the exposure. For female rats, the increase in escape response began about day 15 

40 of exposure. Male rats showed an increased spontaneous fighting response late in the exposure. 

41 During the last 5 days of exposure, female rats in the avoidance escape study showed a fine 

42 tremor and some weight loss. The behavioral changes were reversed during a 60-day recovery 

43 period. At autopsy following exposure, two of three female rats that exhibited behavior changes 

44 had histological changes in the medulla oblongata of the central nervous system, consisting of 

45 perivascular cuffing by lymphocytes. These lesions were less severe in rats sacrificed after the 

46 recovery period. No lesions were observed in the lung, liver, or kidney. Male rats also showed 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 18 of 51

1 infiltration of lymphocytes in the central nervous system. The concentration of mercury was 

2 measured with a vapor analyzer.

3

4 In the second study (Kishi et al. 1978), male rats (two groups of seven, strain unspecified) 

exposed to 3.0 mg/m3 5 (0.37 ppm) mercury vapor for 3 hours/day, 5 days/week for 12 to 42 weeks 

6 exhibited behavioral changes and gained less weight than a control group. When tested during 

7 the weeks of exposure, rats showed a decline in avoidance response and an increase in escape 

8 latency. The time to onset of these effects varied from 12 to 39 weeks. Tremors were first 

observed during the 18th 9 week of exposure. All rats recovered to a normal rate of responding and 

10 normal latency within 12 weeks after termination of exposure. Rats sacrificed at the end of 

11 exposure showed slight degenerative changes in the tubular epithelium of the kidney, but no 

12 changes in the lung, liver, or brain. Tissues of rats sacrificed after recovery were normal.

13

14 Slight tremors and clonus were observed in two of six male rabbits that inhaled an 

analytically determined average concentration of 4.0 mg/m3 15 (0.49 ppm) mercury vapor for 6 

16 hours/day, 4 days/week for 13 successive weeks (Fukuda 1971). These signs were observed at 

17 the end of the weeks of exposure.

18

19 3.4. Developmental/Reproductive Toxicity

20

21 Reproductive and developmental toxicity studies including developmental neurotoxicity 

22 studies and fetal and neonatal tissue concentrations of mercury are summarized in Table 5.

23

24 Mercury vapor penetrates the maternal placental and blood-brain barrier of the developing

25 fetus. Mercury associated with metallothionein accumulates in the placenta. Following in utero 

26 exposure, mercury concentrations in fetal organs are lower than those of respective maternal 

27 organs (Khayat and Dencker 1982; Yoshida et al. 1986; Brambila et al. 2002). 

28

Pregnant squirrel monkeys were exposed to either 0.5 or 1.0 mg/m3 29 (0.06 or 0.12 ppm) of 

30 mercury vapor for either 4 or 7 hours/day (Newland et al. 1996). Exposures were conducted for 

31 5 days/week between weeks 3 and 22 of gestation, for a total number of exposure days ranging 

32 from 63-79 (gestation period of 154 days). None of the six tested offspring was prenatally 

33 exposed over exactly the same period of gestation. Offspring were selected from “uneventful” 

34 pregnancies. The offspring were 0.8 to 4 years of age when evaluated in a lever-press test. 

35 Exposure-related increases in performance variability and longer lever-press duration were 

36 reported, with one offspring displaying “erratic” behavior, but results were extremely variable 

37 among and between the controls and exposed groups. 

38

39 Soderstrom et al (1995) exposed groups of eight pregnant Sprague-Dawley rats to 1.5 

mg/m3 40 for 1 or 3 hours/day, either early in pregnancy (gestation day [GD] 6-11) or late in 

41 pregnancy (GD 13-18). There was no effect on body weight of the dams or neonates, and clinical 

42 signs and development of the offspring observed at postnatal day 2-3 were normal. A group of 

43 offspring were sacrificed on PND 2-3 for examination of mercury in different areas of the brain. 

44 Additional groups were sacrificed on PNDs 21 and 60, and areas of the brain were analyzed for 

45 nerve growth factor and its low- and high-affinity receptors (mRNA coding for nerve growth 

46 factor) as well as choline acetyltransferase activity. On day 2-3 postexposure, mercury 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 19 of 51

1 concentrations in brain of the neonate control and 1-hour and 3-hour exposure groups were 1, 4, 

2 and 11 ng/g wet weight, respectively (it is assumed this is for both early and late pregnancy 

3 exposures). Following the higher exposure during early pregnancy, nerve growth factor was 

4 increased in the hippocampus area of the brain and decreased in the basal forebrain and septal 

5 area on PND 21. mRNA was reduced in the basal forebrain. The authors suggested neuronal 

6 damage and disturbed trophic regulation during development.

7

8

TABLE 5. Reproductive, Developmental, and Developmental Neurotoxicity Studies in Laboratory Animals

Species Concentration/

Duration/Age

Effect Reference

Reproductive

Rat (1) Pre-breeding: 1, 2, or 

4 mg/m3 2 h/d, 11 

consecutive days;

(2) 1 or 2 mg/m3 8 days 

prior to and 8 days after 

breeding

(1) Estrous cycle and hormone level changes 

secondary to general toxicity at 4 mg/m3

;

(2) No significant effect on pregnancy rate or 

pregnancy maintenance

Davis et al. 2001

Developmental/Neurotoxicity

Monkey 0.5, 1.0 mg/m3,

4 or 7 h/d

between gestation wk 3 

and 22

Exposure-related, but variable performance 

in lever-press test in adulthood

Newland et al. 1996

Rat 1.5 mg/m3,

1 or 3 h/d

GD 6-11 or 13-18

No clinical signs; no developmental effects; 

nerve growth factor increased or decreased 

in different areas of the brain

Söderstrom et al. 1995

Rat 1.8 mg/m3,

1 or 3 h/d

GD 11-14 or 17-20

No clinical signs and no effect on maturation 

endpoints of offspring. Neurotoxicity tests 

indicated reduced ability to adapt; 

hypoactivity at 3 months and hyperactivity at 

14 months, but no effect 11 months later; no 

effect on swim maze test

Danielsson et al. 1993

Rat 1.8 mg/m3,

1.5 h/d, 

GD 14-19

No effect on clinical signs or developmental 

markers of offspring; hyperactivity in 

spontaneous motor activity and latencies in 

some maze tests at 4-5 months of age; 

mercury concentration in brain at 2-3 days 

postpartum: 5±2 μg/kg wet weight

Frederiksson et al. 1996

Rat 1, 2, 4, or 8 mg/m3,

2 h/d,

GD 6-15

Concentration-related increases in fetal 

tissue concentrations of mercury after 5 and 

10 days; maternal and fetotoxicity at 8 

mg/m3 (dams became moribund by PND 1); 

decreased weight gain (7%) in the dams in 

the 4 mg/m3 group 

Morgan et al. 2002;

Brambila et al. 2002

Rat 4 mg/m3,

2 h/d,

GD 6-15

No effect on responses of peripheral nerves, 

somatosensory (cortical and cerebellar), 

auditory or visual modalities when tested on 

PNDs 140-168

Herr et al. 2004

Rat 0.05 mg/m3, 

1 or 4 h, 

neonatal days 11-17

No clinical signs; changes in motor activity 

and learning in one test, tested at 2-6 months 

of age

Fredriksson et al. 1992

9 GD = gestation day.
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 20 of 51

1

2

Groups of 12 pregnant Sprague-Dawley rats inhaled 0 or 1.8 mg/m3 3 (0.22 ppm) mercury 

4 vapor for 1 hour (defined as the low-dose group) or 3 hours (high-dose group) during GD 11-14 

5 and 17-20 (Danielsson et al. 1993). These concentrations were not maternally toxic. On days 2-

6 3 postpartum, three offspring from each group were sacrificed and the brain, liver, and kidney 

7 were analyzed for mercury. There were statistically significant dose-related elevated amounts of 

8 mercury in all organs analyzed except for brain in the low-dose group. 

9

10 Additional groups of offspring in this study (Danielsson et al. 1993) were examined for 

11 maturation endpoints as well as activity and learning. There were no differences in body weight, 

12 maturation variables, or clinical signs between exposed and control offspring. Treated offspring 

13 were hypoactive for spontaneous motor activity when tested at 3 months of age but hyperactive at 

14 14 months. In a radial arm maze learning test (for a food reward), prenatally exposed rats 

15 showed retarded acquisition of spatial learning. However, there were no differences between 

16 control and exposed groups in learning ability in a swim maze. In a test of habituation to a novel 

17 environment, prenatally exposed rats showed a reduced ability to adapt. When tested at 11 

18 months after the initial tests, there were no differences in activity among the control and exposed 

19 groups of offspring. 

20

Fredriksson et al. (1996) exposed 12 pregnant Sprague-Dawley rats to 1.8 mg/m3 21 (0.22 

22 ppm) mercury vapor for 1.5 hours/day during GD 14-19. Additional groups were administered 

23 methyl mercury by gavage (2 mg/kg/day over GD 6-9) or both methyl mercury and mercury 

24 vapor at the described doses. Compared to a control group, treated offspring (all groups) showed 

25 no differences in clinical parameters or developmental markers. Surface righting reflex and 

26 negative geotaxis were unaffected within a few days after birth. When tested at 4-5 months of 

27 age, offspring treated with mercury vapor alone showed hyperactivity in spontaneous motor 

28 activity (locomotion, rearing, and total activity) and longer latencies in swim and radial arm maze 

29 tests. Results in some tests were conflicting as latency was shown in the swim maze on the 

30 second test day of two consecutive days of testing but not on the first day. Exposure to 

31 methylmercury did not alter these functions, but coexposure to methylmercury and mercury 

32 vapor increased the mercury vapor-induced deficits.

33

34 Pregnant Long-Evans rats were exposed nose-only to analytically-determined 

concentrations of 0, 1, 2, 4, or 8 mg/m3 35 of mercury vapor for 2 hours/day from GD 6 through 15 

36 (Morgan et al. 2002). Initial groups consisted of 25 rats, with sacrifices on GD 6, 10, and 15 and 

37 1 week after the last exposure. Maternal toxicity, described as concentration-related decreases in 

38 weight gain and mild nephrotoxicity (increased urinary protein and alkaline phosphatase, but not 

glucose), were observed in rats exposed to 4 and 8 mg/m3

. Dams exposed to 8 mg/m3 39 exhibited 

40 mild tremor and unsteady gait (day of onset not stated), and were euthanized in moribund 

41 condition on postnatal day (PND) 1. There was no histopathological evidence of toxicity in 

maternal lung, liver, or kidney of any rats exposed to 1, 2, 4, or 8 mg/m3 42 at GD 6 or 15, or 

43 PND 1. Metallothionein and glutathione S-transferase activity levels were increased in the 

kidney, lung, and brain of maternal animals (measured only in the 4 mg/m3 44 group), but not in the 

45 tissues of neonates. [Glutathione transferase activity was higher in pregnant rats than in a group 

46 of concurrent control non-pregnant rats (Brambila et al. 2002)]. Developmental effects were 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 21 of 51

confined to the 8 mg/m3 1 group and consisted of increased resorption, decreased litter size, and 

2 decreased PND 1 neonatal weight. Neonatal organ weights were not affected by exposure. 

3 Mercury levels in brain, liver, and kidney of neonatal rats increased with increasing number of 

4 exposure days and increasing exposure concentration. At the end of the 10-day exposure, 

5 concentrations were highest in the fetal liver followed by the kidney and brain. In 

transplacentally-exposed neonates of dams exposed to 4 mg/m3 6 , mercury accumulation in the 

7 kidney was approximately 1000-fold less than in the kidney of dams. The authors stated that 

8 adverse effects of mercury on developmental outcome occurred only at a concentration that 

9 caused maternal toxicity.

10

11 The effect of mercury vapor exposure on neuronal function of the above gestationally12 exposed rats was reported by Herr et al. (2004). The study was limited to effects on offspring of 

pregnant Long Evans rats exposed nose-only to 0 or 4 mg/m3 13 for 2 hours/day on GD 6 through 

14 15. The authors stated that this is approximately a maximal tolerated dose for the dams. 

15 Offspring (one female and one male per dam) were tested between postnatal days 140-168 using 

16 a battery of sensory evoked potentials. Peripheral nerve action potential, nerve conduction 

17 velocity, somatosensory evoked responses (cortical and cerebellar), brainstem auditory evoked 

18 responses, pattern evoked potential, and flash evoked potential were quantified. None of the 

19 evoked responses were significantly altered. On PND 1, fetal brains contained approximately 20 

20 ng/g total mercury (controls, approximately 1 ng/g).

21

22 Fredriksson et al. (1992) exposed groups of 10 neonatal Sprague-Dawley rats to an 

analytically-determined concentration of 0.05 mg/m3 23 (0.006 ppm) for 1 hour (low exposure) or 4 

24 hours (high exposure) daily from days 11-17 of age. This period of time is considered a period of

25 rapid brain growth in rats. Rats were tested for behavioral changes at 2-6 months of age. Tests 

26 included spontaneous motor activity (locomotion, rearing, and total activity) and learning (radial 

27 arm maze and swim maze). No clinical signs were observed during the exposure days and there 

28 was no weight change. Tested motor activity was variable between ages (two and four months) 

29 and over the one-hour observation time (broken into three 20-minute sessions). At two months 

30 of age, rats exposed to the low dose showed no difference in motor activity compared with 

31 controls; whereas, the rats exposed to the high dose showed an increase in locomotion and total 

32 activity and a decrease in rearing. At four months of age, the low-dose rats showed increased 

33 locomotion and total activity and decreased rearing; the high-dose rats showed a marked 

34 hypoactivity in all three motor activity tests. In the radial-arm maze, tested over 2 days at 6 

35 months of age, rats showed a concentration-dependent impairment in learning. Learning 

36 improved over the two-day test for the control and low-exposure groups, but not for the high37 exposure group. There was no difference among control and treated groups in the swim maze 

38 test.

39

40 Female reproductive toxicity was studied by Davis et al. (2001) by exposing female 

Sprague-Dawley rats, nose-only, to 0, 1, 2, or 4 mg/m3 41 mercury vapor for 2 hours/day for 11 

consecutive days. A two-hour exposure to 4 mg/m3 42 for 11 days resulted in a 22% weight 

43 decrease relative to controls (weight decreases following 1, 4, and 7 days were 1, 4, and 8%, 

respectively). Estrous cycles were slightly prolonged in the 2 and 4 mg/m3 44 dose groups, and 

45 serum estradiol and progesterone levels were significantly decreased and increased, respectively, 

in the 4 mg/m3 46 group compared to controls. These effects were attributed to body weight loss 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 22 of 51

1 and general toxicity. In an evaluation of pregnancy outcome, female rats were exposed to 1 or 2 

mg/m3 2 of mercury vapor, 2 hours/day for 8 days prior to breeding or 8 days after breeding. There 

3 was no effect on pregnancy rate or numbers of implantation sites.

4

5 3.5. Genotoxicity

6

7 Genotoxicity studies were reviewed by ATSDR (1999). Most of the studies addressed 

8 the genotoxicity of organic mercury compounds. Studies with inorganic mercury were usually 

9 performed with mercuric chloride. Mercuric chloride was not mutagenic in the Salmonella 

10 typhimurium plate incorporation assay (strains TA98, TA102, TA1535, and TA1537). However, 

11 mercuric chloride can damage DNA in rat and mouse embryo fibroblasts. A dose-related 

12 increase in chromosome aberrations was observed in the bone marrow of mice administered 

13 mercuric chloride orally at doses up to 4.4 mg/kg, but not in mice injected intraperitoneally at 

14 similar doses. In vitro, mercuric chloride increased chromosome aberrations in Chinese hamster 

15 ovary cells. From these studies, ATSDR concluded that, although the data are mixed, inorganic 

16 mercury compounds have some genotoxic or clastogenic potential.

17

18 3.6. Chronic Toxicity/Carcinogenicity

19

20 Ashe et al. (1953) reported that there was no histopathological evidence of respiratory 

damage in 24 rats exposed to 0.1 mg/m3 21 of mercury vapor for 7 hours/day, 5 days/week for 72 

22 weeks. The U.S. EPA considers the evidence for both animal and human carcinogenicity 

23 inadequate (U.S. EPA 1995). Their classification is D - not classifiable as to human 

24 carcinogenicity. 

25

26 3.7. Summary

27

Recently conducted studies show that a 1-hour exposure of mice to 9.8 mg/m3 28 mercury 

29 vapor resulted in lung damage (Shimojo et al. 1996); whereas, a 2-hour exposure of pregnant rats 

to 8 mg/m3 30 was a NOAEL for lesions of the lung, liver, and kidney when examined immediately 

after exposure (Morgan et al. 2002). The 2-hour exposure to 8 mg/m3 31 resulted in a decreased 

32 weight gain compared with controls and mild nephrotoxicity as indicated by urinary enzymes. A 

one-hour exposure of rats to approximately 26.7 mg/m3 33 resulted in lung lesions, but no deaths; a 

2-hour exposure to 27 mg/m3 34 resulted in death of 20 of 32 rats (Livardjani et al. 1991). There 

35 were no lesions of the lung, liver, or kidney in non-pregnant and pregnant female rats exposed to 

4 mg/m3 36 for 2 hours/day for 1 or 10 days (Brambila et al. 2002; Morgan et al. 2002). Kidney 

lesions were not found in neonates exposed in utero to 4 mg/m3 37 . Developmental effects were 

observed only in association with maternal toxicity, following repeated exposure to 8 mg/m3 38 .

39

40 Reversible behavioral changes were observed in male and female Wistar-derived rats 

exposed to 17.2 mg/m3 41 (2.1 ppm) for 2 hours/day, 5 days/week for 22 exposures over 30 days 

(Beliles et al. 1968) and 14 male rats (strain unspecified) exposed to 3.0 mg/m3 42 (0.37 ppm) for 3 

43 hours/day, 5 days/week for 12 to 42 weeks (Kishi et al. 1978). Following a recovery period, 

44 lesions were observed in the central nervous system in some rats in the first study and in the 

45 kidney in the second study.

46
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 23 of 51

1 Developmental neurotoxicity tests with rats involving 6-8 daily 1-4-hour exposures at 

concentrations as low as 0.05 mg/m3 2 (0.006 ppm) were associated with altered spontaneous 

3 motor activity and decrements in learning tasks (Fredriksson et al. 1992; 1996; Danielsson et al. 

4 1993). The study with squirrel monkeys (Newland et al. 1996) clearly shows effects but does not 

5 provide sufficient information about the shape that a dose-response relationship might assume, 

6 and it did not identify a no-effect level. 

7

8 Genotoxicity studies, usually conducted with mercuric chloride, demonstrated mixed 

9 results; none of the studies used the inhalation method of administration. According to ATSDR 

10 (1999), inorganic mercury compounds may have some genotoxic or clastogenic potential. No 

11 recent chronic toxicity/carcinogenicity studies have been conducted with laboratory animals. 

12

13 4. SPECIAL CONSIDERATIONS

14 4.1. Metabolism and Disposition

15

16 A review of animal and human studies indicates that 70-80% of inhaled mercury is 

17 absorbed into the lungs, primarily in the alveolar-interstitial region (Leggett et al. 2001; AIHA 

18 2002). Deposition in the lungs is controlled by the rate of breathing (Hayes and Rothstein 1962). 

19 As an uncharged monatomic gas, mercury is highly diffusible and lipid soluble. The lipophilic 

20 vapor is readily absorbed into the bloodstream; from there it diffuses to all tissues in the body 

21 (Goyer and Clarkson 2001). In erythrocytes it is rapidly oxidized by cytosolic catalase-hydrogen 

peroxide to mercuric mercury (Hg+2 22 ). Mercuric mercury is highly reactive and rapidly combines 

23 with intracellular ligands such as sulfhydryls, potentially disrupting enzymes and proteins 

24 essential to normal organ function. It may also form complexes with glutathione which are then 

25 secreted in the bile. The presence of mercury in the body induces thiol-containing proteins, the 

26 metallothioneins. Induction of metallothioneins (regulated by at least two genes, MT-1 and MT27 II) is believed to be a protective mechanism. Metallothioneins are induced in the kidney and 

28 placenta of rat dams exposed during gestation (Brambila et al. 2002; Morgan et al. 2002) and in 

29 fetal rat brain following in utero exposure (Aschner et al. 1997). 

30

31 A small amount of elemental mercury may be transported to tissues including the brain 

32 where biotransformation takes place. Elemental mercury traverses the blood-brain barrier more 

33 readily than mercuric ions. Mercury is absorbed by all tissues, but the primary organs of 

34 deposition are the brain and kidneys (Goyer and Clarkson 2001). Deposition in tissues is linearly 

35 related to exposure time and atmospheric concentration. Clearance half-times of inhaled mercury 

36 by human subjects range from 1.7 days for the lungs to 64 days for the kidney region (Hursh et 

37 al. 1976). Mercury absorbed by human skin was estimated to be 2.2% of that absorbed by the 

38 lung (Hursh et al. 1989). Excretion is in the urine and feces; only a small portion is excreted in 

39 the expired air.

40

The biokinetics of inhaled mercury vapor (Hg0 41 ) have been studied in human subjects. 

42 These studies are summarized in Table 6 and blood concentrations are summarized in Table 7. 

Exposure concentrations and durations ranged from 0.10 mg/m3 43 (0.007 ppm) for 7 hours 

(Teisinger and Fiserova-Bergerova 1965) to 0.40 mg/m3 44 (0.049 ppm) for 15 minutes (Sandborgh45 Englund et al. 1998). No adverse effects were reported in these studies. The most recent, well46 conducted study in which known extraneous sources of mercury were minimized is described. 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 24 of 51

1 Additionally, a monitoring study is included in Table 7. Blood mercury in control subjects is 

2 generally below 50 ng/mL and urine mercury is generally below 25 μg/L (Goldwater 1972). 

3

TABLE 6. Human Metabolism Studies

Concentration

(Subjects)

Exposure 

Duration Observation Reference

0.050-0.35 mg/m3

(3 male, 1 female 

subjects)

5 mina 70-85% absorption Nielsen Kudsk 1965

0.06-0.11 mg/m3

(5 male subjects)b

14-24 min 74% retention; 7% expired; tissue halflives; lung, 1.7 days, head, 21 days Hursh et al. 1976;

Cherian et al. 1978

0.06-0.40 mg/m3

(5 male subjects; 3 

ingested 65 mL 

ethanol)b

11-21 min 73% retention; lower Hg retention 

(55%) following ingestion of ethanol

Hursh et al. 1980

0.4 mg/m3

(9 males, females; 

light physical 

exercise at 50 W)c

15 min rapid absorption; 67% retention; 7.5-

12% loss by expiration in 3 days; blood 

plasma half-life of 10 days 

Sandborgh-Englund et 

al. 1998

0.10 mg/m3

(4 subjects); 0.20 

mg/m3 (1 subject)c

7 h 76% retention; urinary excretion 

(g/24 hours) approximated nonexposed values

Teisinger and FiserovaBergerova 1965

0.01-0.106 mg/m3; 

mean 0.04 mg/m3

 

(10 workers)

8 h, 5 d blood Hg concentration of 2.0 g/dl; 

urinary Hg concentration of 50 g/g 

creatinine

Roels et al. 1987

a 4 Exhaled air was collected for 5 minutes; it is assumed the exposures were also for 5 minutes. b 5 Subjects inhaled through a mouthpiece.

C 6 Nasal inspiration and oral expiration.

7

8

9 Sandborgh-Englund et al. (1998) described the absorption, blood levels, and excretion of 

10 mercury vapor after a single exposure in humans. Nine healthy volunteers, two males and seven 

females, ages 19-53, inhaled 0.4 mg/m3 (analytically determined range of 0.365 to 0.430 mg/m3 11 ) 

12 of mercury vapor through a reverse valve mouthpiece for 15 minutes. None of the subjects had 

13 amalgam fillings, and fish had been excluded from the diet for the previous month. The subjects 

14 exercised on a bicycle ergometer at 50 W. The median retention was 69% of the inhaled dose 

15 (range 57-73%). During the following three days, 7.5-12% of the absorbed dose was lost by 

16 exhalation, with a median half-life of mercury in expired breath of two days. Absorption by 

17 blood and plasma was rapid, followed by a bi-exponential decline in both media. Substantial 

18 inter-individual variation was observed in the area under the concentration-time curves for blood 

19 and plasma. About 1% of the absorbed dose was excreted via the urine during the first 3 days 

20 after exposure, and an estimated 8-40% was excreted during 30 days. Total mercury in blood 

21 (plasma and erythrocytes combined) increased from a baseline value of 6.0 nmol/L (range 4.0-7.6 

22 nmol/L) to a maximum concentration of 7.4 nmol/L (median net value; 25-75 percentile of 6.6-

23 8.9 nmol/L). Blood samples were taken from 15 minutes up to 8 hours after the beginning of the 

24 exposure. The maximum blood concentration was reached 5 hours after the beginning of 

25 exposure. Baseline blood samples were composed of primarily methyl mercury.

26
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 25 of 51

1 Jonsson et al. (1999) used the data of Sandborgh-Englund et al. (1998) to model the 

2 kinetics of mercury vapor in humans. A four-compartment model, including two depot 

3 compartments to account for retention in lungs and kidneys, respectively, gave the best fit to the 

4 data. The median half-time in the respiratory depot compartment was estimated at 1.8 days; the 

5 median half-life in the excretion depot was estimated at 63 days.

6

7 Barregard et al. (1996) observed two phases of elimination in workers following an initial 

8 high unquantified exposure to Hg vapor. Workers were also exposed to inorganic Hg 

9 compounds and lead. Monitoring followed 2-10 days of exposure, 7 hours/day, after which signs 

10 and symptoms of Hg intoxication appeared. The half-life of the fast phase was 2-16 days and the 

11 half-life of the slow phase was more than a month. The authors attributed the fast phase to 

12 exceedence of the capacity of the Hg binding sites in the kidney.

13

14 Roels et al. (1987) monitored workers at an alkaline battery manufacturing plant. 

15 Monitoring was performed daily with personal samplers for 8-hour periods for 5 days. 

Atmospheric concentrations ranged from 0.010 to 0.106 mg/m3 (overall mean 0.040 mg/m3 16 ). 

17 Blood mercury concentrations taken at the end of the work shift averaged 2.0 g/dl (20 g/L) 

18 and urine samples collected the following morning averaged 50 g/g creatinine (values estimated 

19 from graphs).

20

21 Falnoga et al. (1994) followed the uptake of mercury in tissues and organs of male adult 

22 Wistar rats placed in the working area of a mercury mine for 38 days. Average air concentrations 

were 0.57 (0.50-0.70) mg/m3 23 . Blood samples, taken at 4, 8, and 18 hours into the exposure, were 

24 209, 256, and 479 ng/g, respectively (approximately 0.21, 0.26, and 0.48 g/mL, respectively); 

25 the control value was 11.6 ng/g. Blood concentrations leveled off at 1 to 1.5 days into the 

exposure (647-776 ng/g), but were higher on the 38th 26 day of exposure (880 ng/g). Following 

exposure of rats to a slightly higher concentration, 1.1 (0.55-1.72) mg/m3 27 for 17 days, elimination 

28 from organs and tissues was complete in 46 days. The authors described uptake into the blood as 

29 irreversible zero order kinetics and elimination from the blood by irreversible first order kinetics. 

The authors stated that several rats died during the exposure to 1.1 mg/m3 30 , but gave neither the 

31 number of rats nor day of death. 

32

Neonatal rats were exposed to mercury vapor, 0.05 mg/m3 33 for 1 or 4 hours/day, from days 

34 11 to 17 of age; sacrifice took place on day 25 (Fredriksson et al. 1992). Mercury concentrations 

35 (mg/kg) in tissues of the control, 1-hour, and 4-hour exposure groups were: brain, 0.002, 0.002, 

36 and 0.002; liver, 0.017, 0.084, and 1.247; and kidney, 0.063, 0.219, and 6.734, respectively. 

37 These concentrations were measured approximately one week after exposure. Nursing infants 

38 may be exposed via consumption of contaminated breast milk from nursing mothers exposed via 

39 the occupational or diet sources (ATSDR 1999). 

40

Adult Wistar rats of either sex inhaled 0.5, 1.0, or 2.0 mg/m3 41 for 1, 2, or 3 hours (nine 

42 exposure groups) (Halbach and Fichtner 1993). Tissue concentrations, determined immediately 

43 after exposure, increased linearly with exposure time or with Hg concentration in air. For 

example, following inhalation of 0.5 mg/m3 44 for 1, 2, or 3 hours, brain concentrations were 7, 12, 

and 15 μg/kg, respectively. Following inhalation of 0.5, 1, or 2 mg/m3 45 for one hour, brain 

46 concentrations were 7, 12, and 18 μg/kg, respectively. Concentrations were highest in the lung. 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 26 of 51

1

2 Although the transport of mercuric ions is limited at the placental barrier by the presence 

3 of high-affinity binding sites (Dencker et al. 1983), dissolved mercury vapor easily penetrates the 

4 placental barrier and accumulates in fetal tissues. Mercury was elevated in tissues of fetuses of 

5 exposed pregnant rats and monkeys, although the magnitude of accumulation was less than that 

6 seen in the maternal brain (Fredriksson et al. 1992; Danielsson et al. 1993; Warfvinge et al. 1994; 

7 Newland et al. 1996; Morgan et al. 2002; see Section 3.4. for study descriptions). Examples of 

8 fetal uptake in animal models are listed in Table 7.

9

TABLE 7. Tissue Concentrations of Mercurya

Concentration

(Subjects)

Exposure 

Duration Observation/Tissue Concentration Reference

Human Monitoring Studies

0.01-0.106 mg/m3; 

mean 0.04 mg/m3

 (10 

workers – occupational 

exposure)

8 h, 5 d 20 g/L (blood) 

50 g/g creatinine (urinary Hg) 

Roels et al. 1987

Background

(military population 

with dental amalgams)

Chronic 2.55 μg/L (blood, total mercury)

0.54 μg/L (blood inorganic mercury)

3.09 μg/L (urine, total mercury)

2.88 μg/L (urine, inorganic mercury)

Kingman et al. 1998

Background

Exposure: 0.40 mg/m3

(9 healthy volunteers)b

─

15 min

0.19 μg/L (blood, inorganic mercury)

1.20 μg/L (blood, total mercury)

1.48 μg/L (blood, total mercury)

Sandborgh-Englund et 

al. 1998

Background

Fetuses

Infants (<3 months)

─ Total mercury:

Brain: 5 ng/g; kidney: 9 ng/g

Brain: 6 ng/g; kidney: 12 ng/g

Lutz et al. 1996

Rodents

Rat: 4 mg/m3

Non-pregnant

Pregnant

Neonates

10 d, 2 h/d

GD 6-15

PND 21

Kidney (total mercury):

60 μg/g (control: 0.009 μg/g)

86 μg/g (control: 0.019 μg/g)

0.089 μg/g (control: 0.018 μg/g)

Brambila et al. 2002

Rat: 4 mg/m3

Dam

Fetus

10 d, 2 h/d Brain:

Control: 0.002 μg/g

GD 15: 3 μg/g

Control: 0.001 μg/g

GD 15: 0.05 μg/g

Morgan et al. 2002

Rat: 0.05 mg/m3 days 11-17 of age

1 or 4 h/d; 

sacrificed day 25

Brain:

Control: 0.002 μg/g

1 h/d: 0.017 μg/g

4 h/d: 0.063 μg/g

Fredriksson et al. 1992

Rat: 1.8 mg/m3 in utero GD 14-19, 

1.5 h/d Brain: 5 ng/g (measured PND 2-3)

Fredriksson et al. 1996

Guinea pig: 0.2-0.3 

mg/m3

Dam

Neonate

2 h/d, 4 days Brain:

Control: 29 ng/g

Exposed: 95 ng/g

Control: 19 ng/g

Exposed: 17 ng/g

Yoshida et al. 1986

a 10 Concentrations are wet weight.
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 27 of 51

b 1 Mercury measured five hours after exposure (background subtracted); no dental amalgams, fish excluded from diet.

2 GD = gestation day; PND = post-natal day.

3

4 In the study of Morgan et al. (2002), metallothionein and mercury concentrations in 

selected tissues of the dam and fetus were provided following inhalation of 4 mg/m3 5 , 2 

6 hours/day, on GD 6-15. On GD 10, metallothionein concentrations were highest in the placenta 

7 of the dam followed by the kidney, liver, and lung. Due to small size, fetal tissue could not be 

8 weighed separate from the placenta prior to GD 10 and brain tissue could not be separated from 

9 the fetus prior to GD 15. On GD 15, the mean mercury concentration in the developing brain of 

10 the fetus was 49 ng/g (approximately 0.05 μg/g). The mean mercury concentration in the brain 

11 of dams was approximately 3 μg/g, and that of the placenta was 2.4 μg/g. The concentration in 

12 the fetal brain was a factor of approximately 60 lower than that of the dam brain. On PND 21, 

the concentration in the kidney of neonates exposed in utero to 4 mg/m3 13 was 0.089 μg/g, whereas 

14 the concentration in the kidney of the control neonate was 0.018 μg/g. 

15

16 Yoshida et al. (2002) studied the role of metallothionein in maternal-to-fetal distribution 

of mercury in pregnant C57Bl6 mice. Following inhalation of 5.5-6.7 mg/m3 17 for 3 hours during 

18 late gestation, elevated mercury concentration in the placenta was associated with 

19 metallothionein. The authors suggested that metallothionein plays a defensive role in preventing 

20 maternal-to-fetal mercury transfer. In non-exposed and mercury-vapor exposed mice, 

21 metallothionein levels were highest in the liver followed by the placenta. Metallothionein 

22 concentrations were statistically significantly higher in the lung and kidney of exposed dams 

23 compared with the control group. Mercury concentrations were elevated in the fetuses (whole 

24 body) of exposed dams by a factor of 9-10 compared to fetuses of control dams.

25

During late gestation, pregnant Hartley strain guinea pigs were exposed to 0.2-0.3 mg/m3 26

27 for 2 hours/day for 4-11 days (Yoshida et al. 1986). Dams and offspring were sacrificed 

28 immediately after birth. After 4 days of exposure, mercury in brain of offspring was not 

29 increased over control levels; however, concentrations were increased in lung, liver, and kidney. 

30 After ≥5 days of exposure, mercury was increased in all offspring tissues. 

31

Between GD 65 and 76, Hartley strain guinea pigs inhaled 8-10 mg/m3 32 for 150 minutes 

33 (Yoshida et al. 1990). Some dams were sacrificed at 2 hours after exposure and tissue levels of 

34 dams and fetuses were analyzed for mercury. Additional dams were allowed to give birth and 

35 offspring, fostered to unexposed dams, were sacrificed at 5 or 10 days after exposure. Fetal brain 

36 concentrations of mercury were not elevated compared to controls. The highest mercury 

37 concentration was in the liver, largely bound to metallothionein. At 5 to 10 days after exposure, 

38 neonate brain concentrations were elevated 3- to 5-fold compared with current controls. On days 

39 5 and 10, the highest mercury concentrations were found in the kidney, followed by liver, lung, 

40 and brain. The authors suggested that mercury, initially bound to metallothionein in the liver was 

41 redistributed during the neonatal period. In the fetal liver, about 50% of the mercury is bound to 

42 metallothionein (Yoshida et al. 1987).

43
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 28 of 51

1 4.2. Mechanism of Toxicity

2

3 At high levels of exposure, respiratory failure, cardiac arrest, and cerebral edema ensue 

4 (Goyer and Clarkson 2001; WHO 2003). These consequences have been attributed to the 

divalent (Hg+2 5 ) mercury which binds to a variety of enzymes and intracellular proteins including 

6 those of microsomes and mitochondria, producing nonspecific cell injury or cell death (Goyer 

7 and Clarkson 2001). The affinity of mercury for ligands containing sulfhydryl (SH or thiol) 

8 groups results in a glutathione complex which is excreted in the bile. The central nervous system 

9 is probably the most sensitive target for elemental mercury vapor exposure. Within the kidney, 

10 the primary toxic effect is on the epithelial cells of the proximal tubules (ATSDR 1999).

11

12 4.3. Structure-Activity Relationships

13

14 No data were located relevant to structure-activity relationships.

15

16 4.4. Other Relevant Information

17 4.4.1. Species Variability

18

19 No relevant data on species variability were located. The absorption, distribution, and 

20 excretion of mercury in humans and animals have similar aspects (ATSDR 1999). The rate of 

21 inhalation of xenobiotics including that of mercury vapor is related to the ventilation rate and the 

22 inhaled concentration (Hayes and Rothstein 1962; Medinsky and Valentine 2001). Relative to 

23 body weight, rodents have a much higher respiratory rate and cardiac output than humans [the 

24 respiratory rate of the mouse may be up to 10 times that of the human (Witschi and Last 2001; 

25 Kale et al. 2002)]. Respiratory rate and cardiac output are the two primary determinants of 

26 systemic uptake of volatile gases following inhalation exposure. As a result of the greater 

27 respiratory rate and cardiac output, rodents generally receive a greater overall dose than humans

28 at equivalent exposure concentrations. 

29

30 Few data were available to compare concentrations of mercury in human and rodent 

31 tissues. Mercury in brain of 19 human fetuses and 14 infants of less than three months of age at 

32 autopsy averaged 5 and 6 ng/g wet weight, respectively (ranges, 2-9 and ≤2-23 ng/g, respectively)

33 (Lutz et al. 1996). Autopsy results of human infants at birth showed total mercury concentrations 

34 in the cerebral cortex of <1 to 20 ng/g wet weight of tissue (Drasch et al. 1994). The variability 

35 among human young is most likely due to differing diets and number of dental amalgam surfaces 

36 in the mothers. Mercury in control fetal guinea pigs and 5- and 10-day old guinea pigs averaged 

37 13±2, 9±1, and 7±1 ng/g wet weight, respectively (Yoshida et al. 1990). Following in utero

exposure to 10 mg/m3 38 of mercury for 150 minutes, brain concentrations in guinea pigs of the 

39 respective age groups were 14±5, 27±1, and 32-33 ng/g wet weight. Fetal levels were measured 

40 two hours post-exposure. The mean concentrations of mercury in GD 15 fetuses of rat dams 

exposed to 4 mg/m3 41 mercury vapor for 10 days was 49 ng/g. Values could not be provided 

42 following a single exposure, but this study as well as other studies show tissue accumulation with 

43 repeat exposure.

44

45 Exposure of rats during fetal development comprises a subchronic exposure. Ten days of 

46 exposure for 2 hours/day for a total of 20 hours over a 20 day gestation period (Morgan et al. 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 29 of 51

1 2002) comprises 4% of the rat gestational period; whereas, the same exposure scenario comprises 

2 0.3% of the human gestation period of 270 days. 

3

4 4.4.2. Susceptible Populations

5

6 Based on a reconstructed accidental inhalation exposure and results of accidental food 

7 poisoning, infants and children are considered the most susceptible members of the population 

(ATSDR 1999; AIHA 2002). Mercury (Hgo 8 ) rapidly passes the blood-brain barrier and reaches 

9 the fetal brain (Danielsson et al. 1993; Fredriksson et al. 1996). A neurotoxicity study with 

neonatal rats involved repeat exposures (Fredriksson et al. 1992). Exposure to 0.05 mg/m3 10

11 (0.006 ppm) mercury vapor for 4 hours/day for 7 days resulted in changes in activity and learning 

12 in some neurotoxicity tests but not in others.

13

14 Increased mercury uptake of neonates compared with dams may indicate increased 

15 sensitivity. Yoshida et al. (1989) exposed Hartley strain guinea pig dams and 12-hour-old 

neonates to 8-10 mg/m3 16 of mercury vapor for 2 hours. Animals were sacrificed immediately 

17 after the exposure. Catalase activity was determined in blood and liver, and mercury and 

18 metallothionein concentrations were measured in selected tissues. Compared with the respective 

19 control and exposed groups of dams, catalase activity was lower in neonate blood and liver by 

20 factors of 2 (blood) and 5 (liver) in the control group and by factors of 1.3 (blood) and 4 (liver) in 

21 the exposed group. Mercury in plasma of neonates was two to three times higher than 

22 concentrations in maternal plasma, but the concentrations in erythrocytes were similar. Except 

23 for kidney, mercury concentrations in organs of neonates were higher than that of dams, with 

24 brain values of neonates being 12-28% higher. For both control and exposed groups, 

25 metallothionein concentration in the liver was higher in the neonates than in the dams.

26

27 In contrast to neonates, fetal tissues of rats accumulate less mercury than the tissues of 

28 mercury-treated dams (Fredriksson et al. 1992; Danielsson et al. 1993; Warfvinge et al. 1994; 

Newland et al. 1996; Morgan et al. 2002). Following 10 days of exposure to 4 mg/m3 29 , (GD 15) 

30 total mercury in brains of dams and fetal rats were 3300 and 49 ng/g of tissue, respectively 

31 (Morgan et al. 2002).

32

Following exposure of nine healthy male and female volunteers to 0.40 mg/m3 33 for 15 

34 minutes, the maximum blood concentration of mercury did not vary greatly (median, 7.4 nmol/L; 

35 range, 5.9-13.0 nmol/L) (Sandborgh-Englund et al. 1998). The time to maximum blood 

36 concentration varied considerably.

37

Based on simulations of accidental exposure, a concentration of 16 mg/m3 38 was fatal to an 

infant (Campbell 1948), whereas concentrations of 18-43 mg/m3 39 were fatal to 4 of 35 adults 

40 (Tennant et al. 1961; Asano et al. 2000).

41

42 4.4.3. Concentration-Exposure Duration Relationship

43

44 Studies with animal models show that tissue mercury concentration increases with 

45 exposure concentration and exposure duration (Morgan et al. 2002; Yoshida et al. 1986). 

46 However, no data were available to describe a concentration-response relationship. Exponential 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 30 of 51

1 scaling (ten Berge et al. 1986) was used to derive exposure duration-specific values. It has been 

2 shown that the concentration-exposure time relationship for many irritant and systemically acting 

vapors and gases may be described by Cn 3 x t = k, where the exponent n ranges from 0.8 to 3.5. In 

4 the absence of chemical-specific data, an n value of 3 was applied to extrapolate to shorter time 

5 periods, and an n value of 1 was applied to extrapolate to longer time periods to provide AEGL 

6 values that would be protective of human health (NRC 2001). 

7

8 4.4.4. Concurrent Exposure Issues

9

10 Amalgam dental fillings as well as food such as fish constitute major sources of chronic 

11 mercury exposure in humans. Mercury vapor from amalgam dental fillings is a potentially 

12 significant source of exposure to elemental mercury as estimates of daily intake from amalgam 

13 restorations range from 3 to 17 g mercury/day, with the majority of individuals exposed to 5 g 

14 mercury/day. Mercury in whole blood ranges from 2 g/L in the absence of fish consumption to 

15 8 g/L when 2-4 fish meals/week are eaten. The mercury intake from fish is primarily in the 

16 form of methyl mercury (Brune et al. 1991; Barregard 1993; Sandborgh-Englund et al. 1998; 

17 ATSDR 1999; WHO 2003). 

18

19 Catalase inhibitors such as ethanol inhibit the oxidation of elemental mercury to divalent 

20 mercury, thus reducing mercury retention. Human subjects that ingested 65 mL of ethanol prior 

21 to exposure to mercury vapor had reduced mercury retention, an increase in the rapid phase of 

22 vapor loss by expiration, increased mercury storage in the liver, a marked reduction in mercury 

23 uptake by the red blood cells, and the abolition of prompt storage of mercury by the lung. 

24 Similar results were seen with mice and rats (Hursh et al. 1980).

25

26 5. DATA ANALYSIS FOR AEGL-1

27 5.1. Summary of Human Data Relevant to AEGL-1

28

29 Exposure to mercury vapor at low concentrations does not induce irritation or other 

30 warning signs. There is no odor.

31

32 Controlled human exposures during metabolism studies used low concentrations and 

33 short exposure durations. No adverse effects were reported following exposure of healthy adults 

to 0.10 mg/m3 for seven hours (Teisinger and Fiserova-Bergerova 1965) or 0.40 mg/m3 34 for up to 

35 15 minutes, the latter exposure accompanied by light physical exercise (Sandborgh-Englund et al. 

36 1998).

37

38 Under conditions of a reconstructed accidental exposure, high-school-age students 

exposed to an estimated 15 mg/m3 39 for 0.75 hours did not become ill (Shelnitz et al. 1988).

40

41 5.2. Summary of Animal Data Relevant to AEGL-1

42

43 Acute studies with animal models used concentrations that induced effects greater than 

44 those defined by an AEGL-1. Repeat-dose studies, including neurotoxicity studies, resulted in 

45 organ lesions; the time of appearance of these lesions could not be ascertained. 

46
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 31 of 51

1 5.3. Derivation of AEGL-1 Values

2

3 Mercury vapor is odorless and produces no irritation or early warning signs. Accidental 

4 human exposures (Section 2.1) show that even lethal exposures may be tolerated for several 

5 hours without apparent warning signs. Because there are no signs of notable discomfort or 

6 irritation at low concentrations, and studies that document asymptomatic, non-sensory effects 

7 that meet the definition of an AEGL-1 are not available, AEGL-1 values are not recommended 

8 (Table 8).

9

TABLE 8. AEGL-1 Values for Mercury Vapor

10-min 30-min 1-h 4-h 8-h

Not

Recommended

Not

Recommended

Not

Recommended

Not 

Recommended

Not 

Recommended

10

11 6. DATA ANALYSIS FOR AEGL-2

12 6.1. Summary of Human Data Relevant to AEGL-2

13

14 As noted in Section 4.1, no adverse effects were reported following controlled exposures 

of healthy adults to 0.10 mg/m3 15 mercury vapor for seven hours (Teisinger and FiserovaBergerova 1965) or 0.40 mg/m3 16 for up to 15 minutes (Sandborgh-Englund et al. 1998). The 

17 latter exposure was accompanied by light physical exercise.

18

19 In their summary of occupational monitoring studies, the AIHA (2002) notes that 

exposure to mercury vapor concentrations of 0.4-2 mg/m3 20 (0.05-0.25 ppm) Amay result in 

21 symptoms of mercury intoxication after exposures of weeks or longer. Adverse effects have not 

22 been reported for exposure to these concentrations of hours or days.@ Similarly, chronic exposure 

to low concentrations during pregnancy (0.025-0.6 mg/m3 23 ) have failed to show an increase in 

24 miscarriages or stillbirths, but congenital anomalies were non-significantly increased (Elghany et 

25 al. 1997). The increase was not concentration related.

26

27 Concentrations during accidental exposures are generally estimated. Students exposed to 

an estimated 15 mg/m3 28 (1.8 ppm) in an unventilated high-school lab for approximately 0.75 

29 hours did not become ill (Shelnitz et al. 1988). Based on simulations of accidental exposure, a 

concentration of 16 mg/m3 30 for a “few hours” was fatal to an infant (Campbell 1948), whereas 

concentrations of 18-43 mg/m3 31 for several hours were fatal to 4 of 35 adults (Tennant et al. 1961; 

32 Asano et al. 2000).

33

34 6.2. Summary of Animal Data Relevant to AEGL-2

35

36 Pregnant Long-Evans rats exhibited no lesions of the lungs, liver, or kidney after 1, 5, or 

10 two-hour daily exposures to 4 mg/m3 37 mercury vapor, although dams became moribund 

following 10 days of exposure to 8 mg/m3 38 (Brambila et al. 2002; Morgan et al. 2002). 

39 Developmental effects consisting of increased resorptions and decreased litter size were confined 

to the 8 mg/m3 40 exposure group. No effects on pregnancy or offspring were reported in the group 

exposed to 4 mg/m3. Following 10 days of exposure to 4 mg/m3 41 , the mean mercury 

42 concentration in the brain of the developing fetus was lower by 60-fold than that in the brain of 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 32 of 51

the dam (0.05 μg/g vs 3 μg/g). A slight weight loss in the dams following inhalation of 4 mg/m3 1

2 for 10 days was attributed to the repeat nature of the exposure. Pregnancies were uneventful in

squirrel monkeys exposed to 0.5 or 1.0 mg/m3 3 for approximately half of their gestation period, 

4 but offspring tested at 0.8 to 4 years of age showed variable behavioral deficits. 

5

A 1-hour exposure of mice to 9.8 mg/m3 6 greatly increased the protein content of broncho7 alveolar lavage fluid; hemoglobin was present in the fluid at 48 hours, suggesting lung damage 

8 (Shimojo et al. 1996). No deaths were reported within 5 days post-exposure. Liver and kidney 

function were normal in mice that inhaled 5.5-6.7 mg/m3 9 for 3 hours as determined by sacrifices 

up to 7 days later (Yoshida et al. 1999a). Rats exposed to 26.7 mg/m3 10 for 1 hour showed no 

11 breathing difficulties, but exhibited lung lesions (Livardjani et al. 1991). No deaths occurred

12 after the 1-hour exposure; but extension of the exposure for another hour resulted in 62.5% 

13 mortality. 

14

15 In repeat-dose studies, reversible neurotoxicity was observed in rats exposed to 17.2 

mg/m3 16 mercury vapor for 2 hours/day, 5 days/week for 22 exposures (Beliles et al. 1968) or 3.0 

mg/m3 17 for 3 hours/day, 5 days/week for 12 to 42 weeks (Kishi et al. 1978). Rats were held for up 

18 to 12 weeks after cessation of exposure; only minor effects were reported. Developmental 

19 studies with repeated exposures showed variable results and may not be relevant to a single 

20 exposure, as mercury accumulates in the brain with each successive exposure.

21

22 6.3. Derivation of AEGL-2 Values

23

24 Although maternal exposures were for 2 hours/day for 10 days, a single 2-hour exposure 

of pregnant Long-Evens rats to 4 mg/m3 25 mercury vapor (Morgan et al. 2002) was used as the 

26 point of departure for the AEGL-2. This value is a NOAEL for developmental effects. 

27 Developmental effects including increased resorption, decreased litter size and decreased 

neonatal weight were observed at the next highest concentration of 8 mg/m3 28 . Uncertainty factors 

29 for the AEGL-2 are based on a weight of evidence of approach. The following factors were 

considered in deriving an interspecies uncertainty factor: the 4 mg/m3 30 value was a NOAEL for 

31 developmental effects (below the definition of the AEGL-2), the exposures were repeated for 10 

32 days, rodents have a higher respiratory rate and cardiac output compared with humans (resulting 

33 in faster uptake), and human monitoring studies show some effects at concentrations of 0.4 to 2 

mg/m3 34 only with chronic exposure (AIHA 2002). The following factors were considered in 

35 deriving an intraspecies uncertainty factor: the population of fetuses is considered a sensitive if 

36 not the most sensitive population, the protective action of the placenta in sequestering mercury 

[the mean concentration of mercury in the brain of dams exposed to 4 mg/m3 37 for 10 days was 60-

38 fold higher than in the fetal brain (Morgan et al. 2002)], and incidences of miscarriages and 

stillbirths were unaffected in women chronically exposed to 0.025 to 0.6 mg/m3 39 , although 

40 anomalies were statistically non-significantly increased (Elghany et al. 1997). Based on these 

41 factors, interspecies and intraspecies uncertainty factors of 1 and 3 were applied. Application of 

larger uncertainty factors, for example 10 or 30 (resulting in 2-hour values of 0.4 or 0.13 mg/m3 42 ),

43 results in values that are inconsistent with the available human data, including the chronic 

44 exposure of pregnant women in the study of Elghany et al. (1997). In the absence of time-scaling 

information, the resulting 2-hour value of 1.33 mg/m3 45 was time-scaled using default n values of 3 

46 and 1 for shorter and longer exposure durations, respectively (NRC 2001). Time-scaling 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 33 of 51

1 calculations are in Appendix A and values are listed in Table 9 below. A category plot of AEGL 

2 values in relation to toxicity data is shown in Appendix B.

3

TABLE 9. AEGL-2 Values for Mercury Vapor

10-min 30-min 1-h 4-h 8-h

3.1 mg/m3

(0.38 ppm)

2.1 mg/m3

(0.26 ppm)

1.7 mg/m3

(0.21 ppm)

0.67 mg/m3

(0.08 ppm)

0.33 mg/m3

(0.04 ppm)

4

5 The AEGL-2 values are supported by the data of Yoshida et al. (1986). Following 

inhalation of 0.2-0.3 mg/m3 6 , 2 hours/day for 4 days, by guinea pig dams, mercury concentrations 

7 were elevated in the dam brain by a factor of 3.3 (95 vs 29 ng/g) whereas the concentration in the 

8 neonate brain was similar to that of the control (19 and 17 ng/g, respectively).

9

10 7. DATA ANALYSIS FOR AEGL-3

11 7.1. Summary of Human Data Relevant to AEGL-3

12

13 Human data are limited to reconstructions of accidental exposures. One such study 

indicates that students exposed to an estimated 15 mg/m3 14 in an unventilated high-school lab for 

15 approximately 0.75 hours did not become ill (Shelnitz et al. 1988). Longer exposures to similar 

16 concentrations resulted in illness, and exposure to higher concentrations for several hours 

17 resulted in some fatalities (see Table 2).

18

19 7.2. Summary of Animal Data Relevant to AEGL-3

20

Male Wistar rats inhaling 26.7 mg/m3 21 mercury vapor for one hour and observed for up to 

22 15 days exhibited no clinical signs, but exhibited lung edema and necrosis (Livardjani et al. 

23 1991). Extending the exposure period for another hour (at approximately the same 

24 concentration) resulted in 62.5% mortality. Although the study is old, rabbits exposed to 31.3 

mg/m3 25 for 1 hour and held for 6 days showed no mortality, but mild to moderate undefined 

26 changes in the lung, kidney, brain, and heart were observed (Ashe et al. 1953).

27

28 Reversible behavioral changes were observed in male and female Wistar-derived rats 

exposed to 17.2 mg/m3 29 (2.1 ppm) for 2 hours/day, 5 days/week for 22 exposures over 30 days 

(Beliles et al. 1968) and 14 male rats (strain unspecified) exposed to 3.0 mg/m3 30 (0.37 ppm) for 3 

31 hours/day, 5 days/week for 12 to 42 weeks (Kishi et al. 1978). Following a recovery period, 

32 lesions were observed in the central nervous system in some rats in the first study and in the 

33 kidney in the second study.

34

35 7.3. Derivation of AEGL-3 Values

36

The 1-hour non-lethal exposure of rats to 26.7 mg/m3 37 (Livardjani et al. 1991) was used as 

the point of departure for development of AEGL-3 values. The 26.7 mg/m3 38 value was adjusted 

39 by a total uncertainty factor of 3 (an interspecies uncertainty factor of 1 and an intraspecies 

40 uncertainty factor of 3) based on a weight of evidence approach. Larger uncertainty factors result 

41 in values incompatible with the overall data. Reversible behavioral changes were observed in 

male and female Wistar rats inhaling 17.2 mg/m3 42 for 2 hours/day for 22 exposures (Beliles et al. 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 34 of 51

1 1968). The uncertainty factor of 3 is considered sufficient to protect susceptible populations. 

2 Values derived using an intraspecies uncertainty factor of 3 are supported by the non-lethal 

concentrations estimated in accidental exposures [up to 15 mg/m3 3 for 0.75 hours [Shelnitz et al. 

1988; AIHA 2002)] and measured in occupational settings [0.4-2.0 mg/m3 4 (AIHA 2002)]. The 

resulting 1-hour value of 8.9 mg/m3 5 was time-scaled using default n values of 3 and 1 for shorter 

and longer exposure durations, respectively. Because the 8-hour time-scaled value of 1.1 mg/m3 6

7 appears low in comparison to accidental non-lethal exposures and is lower than some chronic 

8 occupational exposures, the 8-hour value was set equal to the 4-hour value. Time-scaling 

9 calculations are in Appendix A and values are listed in Table 10 below. A category plot of 

10 AEGL values in relation to the animal toxicity and human metabolism data is found in Appendix 

11 B.

12

TABLE 10. AEGL-3 Values for Mercury Vapor

10-min 30-min 1-h 4-h 8-h

16 mg/m3

(2.0 ppm)

11 mg/m3

(1.3 ppm)

8.9 mg/m3

(1.1 ppm)

2.2 mg/m3

(0.27 ppm)

2.2 mg/m3

(0.27 ppm)

13

14 The derived values are supported by concentrations estimated during accidental nonlethal exposures. Concentrations of 15 mg/m3 for 0.75 hours and 16 mg/m3 15 for a “few hours” 

16 were not lethal to older children and adults (although one infant death was recorded) (AIHA 

17 2002). The derived values are also supported by the study of Beliles et al. (1968) in which 

18 reversible behavioral changes were observed in male and female Wistar-derived rats exposed to 

17.2 mg/m3 19 mercury vapor for 2 hours/day, 5 days/week for 22 exposures over 30 days. A 

20 histological change in the medulla oblongata comprised of perivascular cuffing by lymphocytes 

21 was partially reversible following a recovery period. This lesion may be attributed to the repeat 

22 exposure protocol. No lesions were observed in other tissues. 

23

24 8. SUMMARY OF AEGLS

25 8.1. AEGL Values and Toxicity Endpoints 

26

27 AEGL values are summarized in Table 11. Because mercury vapor has no odor or 

28 warning properties, AEGL-1 values were not recommended. 

29

30 The point of departure for the AEGL-2 was a single 2-hour exposure of pregnant rats to 4

mg/m3 mercury vapor (Morgan et al. 2002). The exposure to 4 mg/m3 31 was a NOAEL for 

developmental effects in rats. The 4 mg/m3 32 value was adjusted by a total uncertainty factor of 3 

33 (an interspecies uncertainty factor of 1 and an intraspecies uncertainty factor of 3) based on a 

34 weight of evidence approach and the incompatibility of the derived values with monitoring data 

35 if a larger uncertainty factor is used. Based on mercury uptake by the sensitive developing brain 

36 of the fetus, compared with uptake by the brain of the dam, an intraspecies uncertainty factor of 3 

37 was considered sufficient to protect susceptible populations. In the absence of time-scaling 

information, the resulting 2-hour value of 1.33 mg/m3 38 was time-scaled using default n values of 3 

39 and 1 for shorter and longer exposure durations, respectively. 

40

The point of departure for AEGL-3 values was the 1-hour exposure of rats to 26.7 mg/m3 41

42 (Livardjani et al. 1991). A 2-hour exposure at this approximate concentration resulted in 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 35 of 51

significant mortality. The 26.7 mg/m3 1 value was adjusted by a total uncertainty factor of 3 (an 

2 interspecies uncertainty factor of 1 and an intraspecies uncertainty factor of 3) based on (1) faster

3 uptake in rodents compared with humans and (2) the incompatibility with monitoring and 

4 accidental exposure data if a larger uncertainty factor is used. The uncertainty factor of 3 is 

considered sufficient to protect susceptible populations. The resulting 1-hour value of 8.9 mg/m3 5

6 was time-scaled using default n values of 3 and 1 for shorter and longer exposure durations, 

7 respectively.

8

TABLE 11. Summary of AEGL Values for Mercury Vapor

Classification

Exposure Duration

10-min 30-min 1-h 4-h 8-h

AEGL-1a

(Nondisabling)

Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended

AEGL-2

(Disabling)

3.1 mg/m3

(0.38 ppm)

2.1 mg/m3

(0.26 ppm)

1.7 mg/m3

(0.21 ppm)

0.67 mg/m3

(0.08 ppm)

0.33mg/m3

(0.04 ppm)

AEGL-3

(Lethal)

16 mg/m3

(2.0 ppm)

11 mg/m3

(1.3 ppm)

8.9 mg/m3

(1.1 ppm)

2.2 mg/m3

(0.27 ppm)

2.2 mg/m3

(0.27 ppm)

a 9 Mercury vapor is odorless. AEGL-1 values are not recommended because mercury vapor has no odor or warning 

10 properties at concentrations that may cause extensive tissue damage.

11

12

13 8.2. Comparison with Other Standards and Guidelines

14

15 Standards and guidelines for exposure to mercury vapor are summarized in Table 12. 

16 The AIHA (2002) did not develop an Emergency Response Planning Guideline-1 (ERPG-1) 

17 because mercury vapor is odorless and produces no irritation or other early warning signs. The 

18 ERPG-2 was based on a combination of animal studies (Fraser et al. 1934; Kishi et al. 1978; 

19 Livardjani et al. 1991) and nine occupational studies. The occupational exposures involved 

vapor concentrations of 0.05-0.25 ppm (0.41-2.1 mg/m3 20 ) which resulted in symptoms in some 

21 workers after exposures of weeks or longer, but not after periods of hours or days. The ERPG-3 

22 was also based on a combination of controlled laboratory studies with animals and fairly 

23 consistent findings from accidental human exposures.

24

25 The 1-hour Spacecraft Maximum Allowable Concentration (SMAC) is 0.01 ppm

(0.08 mg/m3

), and the 24-hour value is 0.002 ppm (0.02 mg/m3 26 ) (NRC 1996). The lung was 

27 considered the target organ for acute exposure. The 1-hour value was based on an estimated 

LOAEL of 2 mg/m3 28 for 5 hours from reconstruction of accidental exposure of 13 workers. 

29 Uncertainty factors of 10 and the square route of 13 divided by 10 were applied; the latter 

30 number was applied to account for the small number of subjects.

31

The ACGIH (1996) TLV-TWA of 0.025 mg/m3 32 was based on a combination of factors 

33 including a Biological Exposure Index urine mercury level of 35 g Hg/g creatinine collected 

34 prior to an 8-hour work shift. The BEI applies only to exposure to elemental and inorganic forms 

35 of mercury and not to organic mercury exposures. The monitoring data of Roels et al. (1987) 

36 suggests that 50 g Hg/g creatinine is the biological threshold for neurological damage in 

37 workers.

38
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 36 of 51

The NIOSH REL and the OSHA PEL are both 0.05 mg/m3 1 , and the ceiling values 

established by NIOSH and OSHA are both 0.1 mg/m3. The NIOSH IDLH is 10 mg/m3 2 . The 

3 IDLH is based on acute inhalation toxicity data in animals in the study of Ashe et al. (1953). All 

NIOSH and OSHA values have a skin notation. The German MAK is 0.1 mg/m3 4 and the Dutch 

MAC is 0.05 mg/m3 5 . 

6

7 The National Academy of Sciences (NRC 1984) developed Emergency and Continuous 

8 Exposure Limits (EEGLs) for Selected Airborne Contaminants. Their 24-hour EEGL of 0.2 

mg/m3 9 was based on the data of Milne et al. (1970). In that study, four workmen became ill after 

exposure to an estimated 1.1 to 4.0 mg/m3 10 for 2.5 to 5 hours. A shorter-term guideline was not 

11 established.

12

TABLE 12. Extant Standards and Guidelines for Mercury Vapor

Guideline

Exposure Duration

10 min 30 min 1 h 4 h 8 h

AEGL-1 Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended

AEGL-2 3.1 mg/m3 2.1 mg/m3 1.7 mg/m3 0.67 mg/m3 0.33 mg/m3

AEGL-3 16 mg/m3 11 mg/m3 8.9 mg/m3 2.2 mg/m3 2.2 mg/m3

ERPG-1 (AIHA)

a Not appropriate

ERPG-2 (AIHA) 0.25 ppm

(2.0 mg/m3)

ERPG-3 (AIHA) 0.5 ppm

(4.1 mg/m3

)

SMAC (NRC)b 0.01 ppm

(0.08 mg/m3)

PEL-ceiling 

(OSHA)c

0.1 mg/m3

IDLH (NIOSH)d 10 mg/m3

REL-TWA, 

ceiling (NIOSH)e

0.05 mg/m3,

0.1 mg/m3

TLV-TWA

(ACGIH)f

0.025 mg/m3

MAK

(Germany)g

0.1 mg/m3

II(8)

MAC (The 

Netherlands)h

0.05 mg/m3

13 a 14 ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 2002)

15 The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be 

16 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 

17 perceiving a clearly defined objectionable odor. 

18 The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be 

19 exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 

20 symptoms that could impair an individual=s ability to take protective action. 

21 The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be 

22 exposed for up to one hour without experiencing or developing life-threatening health effects. 

23 b 24 SMAC (Spacecraft Maximum Allowable Concentration, National Research Council) (NRC 1996)

25 SMACs are intended to provide guidance on chemical exposures during normal operations of spacecraft as well 

26 as emergency situations. The one-hour SMAC is a concentration of airborne substance that will not compromise 
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 37 of 51

1 the performance of specific tasks by astronauts during emergency conditions or cause serious or permanent toxic 

2 effects. Such exposures may cause reversible effects such as skin or eye irritation, but they are not expected to 

3 impair judgment or interfere with proper responses to emergencies.

4 c 5 OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time 

6 Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no 

7 more than 10 hours/day, 40 hours/week.

8 d 9 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health)

10 (NIOSH 2005) represents the maximum concentration from which one could escape within 30 minutes without 

11 any escape-impairing symptoms, or any irreversible health effects. 

12 e 13 NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits -

14 Time Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA.

15 f 16 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value -

17 Time Weighted Average) (ACGIH 1996) is the time-weighted average concentration for a normal 8-hour 

18 workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, 

19 without adverse effect.

20

21 gMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche 

22 Forschungsgemeinschaft [German Research Association] 2005) is defined analogous to the ACGIH-TLV-TWA. 

23 For mercury, category II(8) indicates an excursion factor of 2, 8 times during the shift.

24

25 hMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 

26 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000)

is defined analogous to the ACGIH-TLV-TWA. The 15-minute peak is 0.5 mg/m3 27 .

28

29 8.3. Data Adequacy and Research Needs

30

31 There are no human data with measured concentrations and symptoms that meet the 

32 definitions of the AEGLs. Human metabolism studies used relatively low and presumably safe 

33 concentrations. The metabolism studies in conjunction with estimated concentrations from non34 fatal human accidental exposures were considered in the development of AEGL values. An 

35 AEGL-1 was not recommended because mercury is odorless and without irritation at 

36 concentrations that may be harmful. The AEGL-2 and AEGL-3 values were based on several 

37 rodent studies that used suitable concentrations and exposure durations. The sensitive 

38 developing fetus was considered in development of AEGL-2 values.

39

40 9. REFERENCES

41

42 ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Documentation 

43 of the Threshold Limit Values and Biological Exposure Indices: Mercury, all forms except 

44 alkyl. Sixth ed. Cincinnati, OH: ACGIH.

45

46 AIHA (American Industrial Hygiene Association). 2002. The AIHA Emergency Response 

47 Planning Guidelines and Workplace Environmental Exposure Level Guidelines Handbook. 

48 Fairfax VA: AIHA.

49
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 38 of 51

1 Asano, S., K. Eto, E. Kurisaki, H. Gunji, K. Hiraiwa, M. Sato, H. Sato, M. Hasuike, N. 

2 Hagiwara, and H. Wakasa. 2000. Acute inorganic mercury vapor inhalation poisoning. 

3 Pathol. Int. 50:169-174. (Summarized in AIHA 2002).

4

5 Aschner, M., F.L. Lorscheider, K.S. Cowan, D.R. Conklin, M.J. Vimy, L.H. Lash. 1997. 

6 Metallothionein induction in fetal rat brain and neonatal primary astrocyte cultures by in 

utero exposure to elemental mercury vapor (Hg0 7 ). Brain Res. 778:222-232.

8

9 Ashe, W.F., E.J. Largent, F.R. Dutra, D.M. Hubbard, and M. Blackstone. 1953. Behavior of

10 mercury in the animal organism following inhalation. Arch. Ind. Hyg. Occup. Med. 7:19-43.

11

12 ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile for 

13 Mercury (update). U.S. Public Health Service. March 1999.

14

15 Barregard, L. 1993. Biological monitoring of exposure to mercury vapor. Scand. J. Work 

16 Environ. Health 19(Suppl. 1):45-49.

17

18 Barregard, L., G. Sallsten, A. Schutz, R. Attewell, S. Skerfving, and B. Jarvholm. 1992. 

19 Kinetics of mercury in blood and urine after brief occupational exposure. Arch. Environ. 

20 Health 47:175-184.

21

22 Barregard, L., G. Quelquejeu, G. Sallsten, J.-M. Haguenoer, and C. Nisse. 1996. Dose23 dependent elimination kinetics for mercury in urine: observations in subjects with brief but 

24 high-level exposure. Int. Arch. Occup. Environ. Health 68:345-348.

25

26 Beliles, R.P., R.S. Clark, and C.L. Yule. 1968. The effects of exposure to mercury vapor on 

27 behavior of rats. Toxicol. Appl. Pharmacol. 12:15-21.

28

29 Brambila, E., J. Liu, D.L. Morgan, R.P. Beliles, and M.P. Waalkes. 2002. Effect of mercury 

30 vapor exposure on metallothionein and glutathione S-transferase gene expression in the 

31 kidney of nonpregnant, pregnant, and neonatal rats. J. Toxicol. Environ. Health, Part A, 

32 65:1273-1288.

33

34 Brune, D., G.F. Nordberg, O. Vesterberg, L. Gerhardson, and P.O. Wester. 1991. A review of 

35 normal concentrations of mercury in human blood. Sci. Total Environ. 100:235-282.

36

37 Campbell, J.S. 1948. Acute mercurial poisoning by inhalation of metallic vapor in an infant. 

38 Can. Med. Assoc. J. 58:72-75. (Summarized in AIHA 2002).

39

40 Cherian, M.G., J.B. Hursh, T.W. Clarkson, J. Allen. 1978. Radioactive mercury distribution in 

41 biological fluids and excretion in human subjects after inhalation of mercury vapor. Arch. 

42 Environ. Health 33:109-114.

43

44 Danielsson, B.R.G., A. Fredriksson, L. Dahlgren, A.T. Gardlund, L. Olsson, L. Dencker, and T. 

45 Archer. 1993. Behavioural effects of prenatal metallic mercury inhalation exposure in rats. 

46 Neurotox. Terat. 15:391-396.
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1

2 Davis, B.J., H.C. Price, R.W. O=Connor, R. Fernando, A.S. Rowland, and D.L. Morgan. 2001. 

3 Mercury vapor and female reproductive toxicity. Toxicol. Sci. 59:291-296.

4

5 Dencker, L., B. Danielsson, A. Khayat, A. Lindgren. 1983. Disposition of metals in the embryo 

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36 Milne, J., A. Christophers, and P. de Silva. 1970. Acute mercurial pneumonitis. Brit. J. Ind. 

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12 NIOSH. 2005. NIOSH Pocket Guide to Chemical Hazards. Online data base, U.S. Department 

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15 NRC (National Research Council). 1984. Emergency and Continuous Exposure Limits for 

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19 NRC (National Research Council). 1996. Spacecraft Maximum Allowable Concentration for 

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23 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute 

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27 O'Neil, M.J., A. Smith, and P.E. Heckelman (Eds.). 2001. The Merck Index, 13th ed. 

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35 absorption, blood levels, and excretion of mercury after a single dose of mercury vapor in 

36 humans. Toxicol. Appl. Pharmacol. 150:146-153.

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38 Schionning, J.D., J.O. Larsen, and R. Edie. 1998. A stereological study of dorsal root ganglion 

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34 Warfvinge, K. J. Hua, and B. Logdberg. 1994. Mercury distribution in cortical areas and fiber 

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38 WHO (World Health Organization). 2003. Elemental Mercury and Inorganic Mercury 

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42 Witschi, H.R. and J.A. Last. 2001. Chapter 15: Toxic Responses of the Respiratory System. In 

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44 McGraw-Hill, p 519.

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10 mercury vapor. Toxicol. Lett. 37:1-6.

11

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18 vapor. J. Trace Elements Exper. Med. 3:219-226. 

19

20 Yoshida, M., M. Satoh, A. Yasutake, A. Shimada, Y. Sumi, and C. Tohyama. 1999a. 

21 Distribution and retention of mercury in metallothionein-null mice after exposure to mercury 

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32 Yoshida, M., C. Watanabe, M. Satoh, A. Yasutake, M. Sawada, Y. Ohtsuka, Y. Akama, and C. 

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34 caused by exposure to mercury vapor at human-relevant concentration. Toxicol. Sci. 80:69-

35 73.

36

37

38
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 45 of 51

1 APPENDIX A: Derivation of AEGL Values

2

3 Derivation of AEGL-1 Values

4

5 Because mercury vapor has no odor or warning properties, AEGL-1 values are not recommended. 

6
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 46 of 51

1 Derivation of AEGL-2 Values

2

3 Key Study: Morgan et al. 2002

4

Toxicity endpoint: A 2-hour/day, 10-day exposure to 4 mg/m3 5 mercury vapor was a NOAEL for 

6 increased resorptions and fetal death in pregnant rats. The next higher

concentration, 8 mg/m3 7 , resulted in fetotoxicity. 

8

Time scaling: Cn 9 x t = k where n = 3 and 1 for shorter and longer exposure periods, 

10 respectively (ten Berge et al. 1986; NRC 2001).

11

12 Uncertainty factors: Total of 3 (weight of evidence approach)

Interspecies: 1, based on the following factors: the 4 mg/m3 13 value was a 

14 NOAEL for developmental effects (below the definition of the AEGL-2), the 

15 exposures were repeated for 10 days, rodents have a higher respiratory rate 

16 and cardiac output compared with humans (resulting in faster uptake), and 

17 human monitoring studies show some effects at concentrations of 0.4 to 2 

mg/m3 18 only with chronic exposure. 

19 Intraspecies: 3, based on the following factors: the population of fetuses is 

20 considered a sensitive if not the most sensitive population, the protective 

21 action of the placenta in sequestering mercury (Morgan et al. 2002), and 

22 incidences of miscarriages and stillbirths were unaffected in women 

chronically exposed to 0.025 to 0.6 mg/m3 23 , although anomalies were 

24 statistically non-significantly increased.

25

Calculations: C/3 = (4 mg/m3)/3 = 1.33 mg/m3 26

C3 27 x t = k

(1.33)

3 x 120 minutes = (282.32 mg/m3

)

3 28 minutes

C1 29 x t = k

1.33 x 120 minutes = 159.6 mg/m3 30 minutes

31

10-minute AEGL-2: C3 x 10 minutes = 282.32 (mg/m3)

3 32 minutes

C = 3.1 mg/m3 33

34

30-minute AEGL-2: C3 x 30 minutes = 282.32 (mg/m3)

3 35 minutes

C = 2.1 mg/m3 36

37

1-hour AEGL-2: C3 x 60 minutes = 282.32 (mg/m3)

3 38 minutes

C = 1.7 mg/m3 39

40

4-hour AEGL-2: C1 x 240 minutes = 159.6 mg/m3 41 minutes

C = 0.67 mg/m3 42

43

8-hour AEGL-2: C1 x 480 minutes – 159.6 mg/m3 44 minutes

C = 0.33 mg/m3 45

46
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 47 of 51

1 Derivation of AEGL-3 Values

2

3 Key Study: Livardjani et al. 1991

4

Toxicity endpoint: Highest 1-hour non-lethal exposure of rats: 26.7 mg/m3 5

6

Time scaling: Cn 7 x t = k where n = 3 and 1 for shorter and longer exposure periods, 

8 respectively (ten Berge et al. 1986; NRC 2001).

9

10 Uncertainty factors: Total of 3 (an interspecies uncertainty factor of 1 and an intraspecies 

11 uncertainty factor of 3), based on (1) faster uptake in rodents compared with 

12 humans and (2) the incompatibility of derived values with monitoring data 

13 and accidental exposure data if a larger uncertainty factor is used. The 

14 intraspecies uncertainty factor of 3 is considered sufficient to protect 

15 susceptible populations. 

16

Calculations: C/3 = (26.7 mg/m3)/3 = 8.9 mg/m3 17

C3 18 x t = k

(8.9 mg/m3)

3 x 60 minutes = (42298.14 mg/m3

)

3 19 minutes

C1 20 x t = k

8.9 mg/m3 x 60 minutes = 534 mg/m3 21 minutes

22

10-minute AEGL-3: C3 x 10 minutes = 42298.14 (mg/m3)

3 23 minutes

C = 16 mg/m3 24

25

30-minute AEGL-3: C3 x 30 minutes = 42298.14 (mg/m3)

3 26 minutes

C = 11 mg/m3 27

28

1-hour AEGL-3: C/3 = 8.9 mg/m3 29

30

4-hour AEGL-3: C1 x 240 minutes = 534 mg/m3 31 minutes

C = 2.2 mg/m3 32

33

8-hour AEGL-3: C1 x 480 minutes - 534 mg/m3 34 minutes

C = 1.1 mg/m3 35 (see below)

36

37 Because of inconsistency with some monitoring data and estimated non-fatal concentrations, the 8-hour 

AEGL-3 value of 1.1 mg/m3 was set equal to the 4-hour value (2.2 mg/m3 38 ).

39
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 48 of 51

1 APPENDIX B: Category Graph of AEGL Values and Toxicity Data

2

3

0.0 

0.1 

1.0 

10.0 

100.0 mg/m3

0 60 120 180 240 300 360 420 480 

Minutes

Human - No Effect

Human - Discomfort

Human - Disabling

Animal - No Effect

Animal - Discomfort

Animal - Disabling

Animal - Some Lethality

Animal - Lethal

AEGL

AEGL Values and Chemical Toxicity Data

Mercury Vapor

AEGL-3

AEGL-2

4

5
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 49 of 51

1 Data:

Category: 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal

Source Species mg/m3 Minutes Category Comments

NAC/AEGL-1 NR 10 AEGL

NAC/AEGL-1 NR 30 AEGL

NAC/AEGL-1 NR 60 AEGL

NAC/AEGL-1 NR 240 AEGL

NAC/AEGL-1 NR 480 AEGL

NAC/AEGL-2 3.1 10 AEGL

NAC/AEGL-2 2.1 30 AEGL

NAC/AEGL-2 1.7 60 AEGL

NAC/AEGL-2 0.67 240 AEGL

NAC/AEGL-2 0.33 480 AEGL

NAC/AEGL-3 16 10 AEGL

NAC/AEGL-3 11 30 AEGL

NAC/AEGL-3 8.9 60 AEGL

NAC/AEGL-3 2.2 240 AEGL

NAC/AEGL-3 2.2 480 AEGL

Nielsen-Kudsk 1965 human 0.05

0.10

0.20

0.35

5

5

5

5

0

0

0

0

metabolism study

Hursh et al. 1976 human 0.11

0.06

24

19

0

0

metabolism study

Hursh et al. 1980 human 0.06

0.40

21

12

0

0

metabolism study

Sandborgh-Englund 

et al. 1998

human 0.40 15 0 metabolism study

Teisinger and FiserovaBergerova 1965human 0.10 420 0 metabolism study

Roels et al. 1987 human 0.04 480 0 occupational monitoring

Morgan et al. 2002 rat 4.0 120 0 no fetotoxicity

Livardjani et al. 1991 rat 26.7

27.0

60

120

2

SL

no deaths;

mild lung lesions

62.5% mortality

Shimojo et al. 1996 mouse 9.8 60 1 increased protein –

broncho-alveolar fluid

Ashe et al. 1953 rabbit 28.7 60 2 mild organ damage

2

3
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 50 of 51

1 APPENDIX C: Derivation Summary

2 MERCURY VAPOR (CAS Reg. No. 7439-97-6)

3

AEGL-1 VALUES

10-min 30-min 1-h 4-h 8-h

Not 

Recommendeda

Not 

Recommended

Not 

Recommended

Not 

Recommended

Not 

Recommended a 4 AEGL-1 values are not recommended because mercury vapor has no odor or warning properties at concentrations 

5 that may cause extensive tissue damage.

6

7

AEGL-2 VALUES

10-min 30-min 1-h 4-h 8-h

3.1 mg/m3 2.1 mg/m3 1.7 mg/m3 0.67 mg/m3 0.33mg/m3

Key Reference: Morgan, D.L., S.M. Chanda, H.C. Price, R. Fernando, J. Liu, E. Brambila, R.W. O=Connor, 

R.P. Beliles, and S. Barone, Jr. 2002. Disposition of inhaled mercury vapor in pregnant rats: 

maternal toxicity and effects on developmental outcome. Toxicol. Sci. 66:261-273.

Test Species/Strain/Number: Rat (pregnant)/Long-Evans/25 (serial sacrifice)

Exposure Route/Concentrations/Durations: Inhalation/0, 1, 2, 4, 8 mg/m3 for 2 hours/day over GD 6-15

Effects: No fetotoxicity observed after 2 hour/day, 10-day exposure to 4 mg/m3. Developmental effects 

including resorptions, decreased litter size and decreased PND 1 weight at 8 mg/m3.

Endpoint/Concentration/Rationale: 2-hour exposure to 4 mg/m3 was a NOAEL for the definition of the AEGL-2, 

i.e., irreversible effects to the fetus.

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3 (based on weight of evidence approach)

Interspecies: 1, based on the following factors: the 4 mg/m3 value was a NOAEL for developmental effects 

(below the definition of the AEGL-2), the exposures were repeated for 10 days, rodents have a higher 

respiratory rate and cardiac output compared with humans (resulting in faster uptake), and human monitoring 

studies show some effects at concentrations of 0.4 to 2 mg/m3 only with chronic exposure (AIHA 2002). 

Intraspecies: 3, based on the following factors: the population of fetuses is considered a sensitive if not the 

most sensitive population, the protective action of the placenta in sequestering mercury (Morgan et al. 2002), 

and incidences of miscarriages and stillbirths were unaffected in women chronically exposed to 0.025 to 0.6 

mg/m3

, although congenital anomalies were statistically non-significantly increased (Elghany et al. 1997). 

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: Cn x t = k where n is 3 and 1 for shorter and longer exposure durations, respectively 

(ten Berge et al. 1986; NRC 2001).

Data Adequacy: The values are supported by occupational monitoring of pregnant women. A study of 

pregnancies in women chronically exposed to mercury vapor (median air concentration, 0.09 mg/m3

; range, 

0.025-0.599 mg/m3

) did not reveal a significant difference from controls regarding miscarriages and

stillbirths, although congenital anomalies were statistically non-significantly increased (Elghany et al. 1997).

8
MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 51 of 51

1

AEGL-3 VALUES

10-min 30-min 1-h 4-h 8-h

16 mg/m3 11 mg/m3 8.9 mg/m3 2.2 mg/m3 2.2 mg/m3

Key Reference: Livardjani, F. M. Ledig, P. Kopp, M. Dahlet, M. Leroy, and A. Jaeger. 1991. Lung and 

blood superoxide dismutase activity in mercury vapor exposed rats: effect of N-acetylcysteine 

treatment. Toxicology 66:289-295.

Test Species/Strain/Number: Rat/Wistar/32

Exposure Route/Concentrations/Durations: Inhalation/0, 26.7 mg/m3 for 1 hour, 27.0 mg/m3 for 2 hours

Effects: 

1-hour exposure to 26.7 mg/m3: no deaths over 15-day observation period; lung lesions

2-hour exposure to 27.0 mg/m3

: death of 20/32 rats 

Endpoint/Concentration/Rationale: NOAEL for lethality: 26.7 mg/m3 for 1 hour meets the definition of the 

AEGL-3

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3 (an interspecies uncertainty factor of 1 and an intraspecies uncertainty factor of 3), 

based on (1) faster uptake in rodents compared with humans, and (2) incompatibility of derived values with 

monitoring and accidental exposure data if larger uncertainty factors are used.

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: Cn x t = k where n is 3 and 1 for shorter and longer exposure durations, respectively (ten Berge et 

al. 1986; NRC 2001). The 8-hour value was set equal to the 4-hour value.

Data Adequacy: Although the data base is not large and data on humans consist of clinical studies and estimated 

concentrations and exposure durations from accidental exposures, a repeat-dose study with the rat (Beliles 

et al. 1968) supports the values. In that study, male and female Wistar-derived rats exposed to 17.2 mg/m3

for 2 hours/day 5 days/week for 22 exposures showed behavioral changes that were reversible following a 

recovery period. Organ lesions consisted of lymphocytic perivascular cuffing of the medulla oblongata. 

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