N AC/Proposed 2 : 1 1 /200 9 1

2

3

4



## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 5



## FOR 6



## MERCURY VAPOR (Hg o 

## ) 7



## (CAS Reg. No. 7439

- 97

- 6) 8

9



## PROPOSED 10

11

12

13

14

15

16

17

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

PREFACE 1

2

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

- 463 of 3

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

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

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

chemicals

. 7

8

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

emergency exposure periods ranging from 10 minutes to 8 hours. Three levels

C AEGL

- 1, 10

AEGL

- 2 and AEGL

- 3

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

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

The three AEGLs are defined as follows: 13

14

AEGL

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

cubic meter [ppm or mg/m 3 ]) of a substance above which it is predicted that the general 16

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

certain asymptomatic, non

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

transient and reversible upon cessation of exposure. 19

20

AEGL

- 2 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 21

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

experience irrevers ible or other serious, long

- lasting adverse health effects or an impaired ability 23

to escape. 24

25

AEGL

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

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

experience life

- threatening health effects or death. 28

29

Airborne concentrations below the AEGL

- 1 represent exposure levels that could produce 30

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

irritation or certain asymptomatic, non

- sensory effects. With increasing airborne concentrations 32

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

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

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

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

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

at concentrations below the corresponding AEGL. 38

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

1

TABLE OF CONTENTS 2

PREFACE

................................ ................................ ................................ ................................ ..................... 2 3

LIST OF TABLES

................................ ................................ ................................ ................................ ........ 5 4

EXECUTIVE SUMMARY

................................ ................................ ................................ ........................... 5 5

1. INTRODUCTION

................................ ................................ ................................ ................................ 7 6

2. HUMAN TOXI CITY DATA

................................ ................................ ................................ ............... 9 7

2.1. Acute Exposures

................................ ................................ ................................ .......................... 9 8

2.1.1. Lethality

................................ ................................ ................................ ................................ ... 9 9

2.1.2. Non lethal Toxicity

................................ ................................ ................................ ................. 10 10

2.2. Occupational Monitoring

................................ ................................ ................................ ........... 11 11

2.3. Neurotoxicity

................................ ................................ ................................ ............................. 11 12

2.4. Developmental/Reproductive Toxicity

................................ ................................ ...................... 11 13

2.5. Genotoxicity

................................ ................................ ................................ ............................... 12 14

2.6. Carcinogenicity

................................ ................................ ................................ .......................... 12 15

2.7. Summary

................................ ................................ ................................ ................................ .... 13 16

3. ANIMAL TOXICITY DATA

................................ ................................ ................................ ............ 13 17

3.1. Acute Studies

................................ ................................ ................................ ............................. 13 18

3.1.1. Rats

................................ ................................ ................................ ................................ ........ 13 19

3.1.2. Mice

................................ ................................ ................................ ................................ ....... 14 20

3.1.3. Rabbits

................................ ................................ ................................ ................................ ... 14 21

3.2. Repeat

- Dose Studies

................................ ................................ ................................ .................. 15 22

3.3. Neurotoxicity

................................ ................................ ................................ ............................. 17 23

3.4. Developmental/Reproductive Toxicity

................................ ................................ ...................... 18 24

3.5. Genotoxicity

................................ ................................ ................................ ............................... 22 25

3.6. Chronic Toxicity/Carcinogenicity

................................ ................................ .............................. 22 26

3.7. Summary

................................ ................................ ................................ ................................ .... 22 27

4. SPECIAL CONSIDERATIONS

................................ ................................ ................................ ........ 23 28

4.1. Metabolism and Disposition

................................ ................................ ................................ ...... 23 29

4 .2. Mechanism of Toxicity

................................ ................................ ................................ .............. 28 30

4.3. Structure

- Activity Relationships

................................ ................................ ................................ 28 31

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

4.4. Other Relevant Information

................................ ................................ ................................ ....... 28 1

4.4.1. Species Variability

................................ ................................ ................................ ................. 28 2

4.4.2. Susceptible Populations

................................ ................................ ................................ ......... 29 3

4.4.3. Concentration

- E xposure Duration Relationship

................................ ................................ .... 29 4

4.4.4. Concurrent Exposure Issues

................................ ................................ ................................ .. 30 5

5. DATA ANALYSIS FOR AEGL

- 1

................................ ................................ ................................ ..... 3 0 6

5.1. Summary of Human Data Relevant to AEGL

- 1

................................ ................................ ......... 30 7

5.2. Summary of Animal Data Relevant to AEGL

- 1

................................ ................................ ........ 30 8

5.3. Derivation of AEGL

- 1 Values

................................ ................................ ................................ ... 31 9

6. DATA ANALYSIS FOR AEGL

- 2

................................ ................................ ................................ ..... 31 10

6.1. Summary of Human Data Relevant to AEGL

- 2

................................ ................................ ......... 31 11

6.2. Summary of Animal Data Relevant to AEGL

- 2

................................ ................................ ........ 31 12

6.3. Derivation of AEGL

- 2 Values

................................ ................................ ................................ ... 32 13

7. DATA ANALYSIS FOR AEGL

- 3

................................ ................................ ................................ ..... 33 14

7.1. Summary of Human Data Relevant to AEGL

- 3

................................ ................................ ......... 33 15

7.2. Summary of Animal Data Re levant to AEGL

- 3

................................ ................................ ........ 33 16

7.3. Derivation of AEGL

- 3 Values

................................ ................................ ................................ ... 33 17

8. SUMMARY OF AEGLS

................................ ................................ ................................ ................... 34 18

8.1. AEGL Values and Toxicity Endpoints

................................ ................................ ...................... 34 19

8.2. Comparison with Other Standards and Guidelines

................................ ................................ .... 35 20

8.3. Data Adequ acy and Research Needs

................................ ................................ .......................... 37 21

9. REFERENCES

................................ ................................ ................................ ................................ ... 37 22

APPENDIX A: Derivation of AEGL Values

................................ ................................ ............................. 45 23

APPENDIX B: Category Graph of AEGL Values and Toxicity Data

................................ ........................ 48 24

APPENDIX C: Derivation Summary

................................ ................................ ................................ ......... 50 25

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

LIST OF TABLES 1

2

S 1. Summary of AEGL Values for Mercury Vapor

................................ ................................ ......................... 7 3

TABLE 1. Chemical and Physical Properties

................................ ................................ ................................ ............ 8 4

TABLE 2. Estimated Human Exposures

- Reconstructions of Accidental Exposures a

................................ ............ 10 5

TABLE 3. Summary of Acute Inhalation Data in Laboratory Animals

................................ ................................ ... 15 6

TABLE 4. Summary of Repeat

- Dose Inhalation Data in Laboratory Animals

................................ ........................ 16 7

TABLE 5. Reproductive, Developmental, and Developmental/Neurotoxicity Studie s in Laboratory Animals

....... 19 8

TABLE 6. Human Metabolism Studies

................................ ................................ ................................ .................... 24 9

TABLE 7. Tissue Concentrations of Mercury

................................ ................................ ................................ ......... 26 10

TABLE 8. AEGL

- 1 Values for Mercury Vapor

................................ ................................ ................................ ....... 31 11

TABLE 9. AEGL

- 2 Values for Mercury Vapor

................................ ................................ ................................ ....... 33 12

TABLE 10. AEGL

- 3 Values for Mercury Vapor

................................ ................................ ................................ ....... 34 13

TABLE 11. Summary of AEGL Values for Mercury Vapor

................................ ................................ ...................... 35 14

TABLE 12. Extant Standards and Guidelines for Mercury Vapor

................................ ................................ ............. 36 15

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

EXECUTIVE SUMMARY 1

2

Mercury vapor, Hg 0 , (CAS Reg. No. 7439

- 97

- 6) is a colorless

, odorless gas generated 3

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

ambient conditions, mercury is a silver

- white, liquid metal. Metallic mercury is non

- flammable 5

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

7

C ontrolled inhalation studies in human volunteers that addressed metabolism used 8

conc entrations that ranged from 0.01 mg/m 3 for 7 hours to 0.40 mg/m 3 for 15 minutes. No 9

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

workplace exposure show s that concentrations of 0.4

- 2 .0 mg/m 3 in indus try result in mercury 11

poisoning only after chronic exposure . C oncentrations of 1.0

- 5.0 mg/m 3 were not unusual in 12

mercury mining operations in the past (AIHA 200 2 ). Additional human data were available from 13

reconstructions of accidental exposures. An est imated airborne concentration of 16 mg/m 3 for a 14

few hours was lethal to an infant; whereas, an estimated concentration of 15 mg/m 3 for 15

0.75 hours failed to induce symptoms of Hg poisoning in high

- school

- age students. 16

17

Animal studies addressed acute and r epeat

- dose toxicity, neurotoxicity, and 18

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

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

Absorbed mercury binds to various proteins, particularly thiol

- containing proteins, resulting in 21

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

spontaneous activity and learning ability) yielded conflicting results. Sufficiently high m ercu ry 23

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

inadequate to determine the carcinogenic potential of mercury vapor. 25

26

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

warnin g properties. Therefore, AEGL

- 1 values are not recommended. 28

29

Although maternal exposures were for 2 hours/day for 10 days, a single 2

- hour exposure 30

of pregnant Long

- Evens rats to 4 mg/m 3 mercury vapor (Morgan et al. 2002) was used as the 31

point of departu re for the AEGL

- 2. This value is a NOAEL for developmental effects. 32

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

neonatal weight were observed at the next highe r concentration of 8 mg/m 3 . Uncertainty factors 34

for the AEGL

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

considered in deriving an interspecies uncertainty factor: the 4 mg/m 3 value was a NOAEL for 36

developmental effects (below the definition of the AEGL

- 2), the exposure s were repeated for 10 37

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

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

mg/m 3 only with chronic exposure (AIHA 20 02). The following factors were considered in 40

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

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

[the mean c oncentration of mercury in the brain of dams exposed to 4 mg/m 3 for 10 days was 60

- 43

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

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

concentration, 0.09 mg/m 3 ; range, 0.025

- 0.60 mg/m 3 ) , although congenital anomalies were 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 7 of 51

statistically non

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

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

uncertainty factors, for example 10 or 30 (resulting in 2

- hour values of 0.4 or 0.13 mg/m 3 ), 3

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

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

- scaling 5

information, the resulting 2

- hour value of 1.3 3 mg/m 3 was time

- scaled using default n values of 3 6

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

8

The AEGL

- 3 values were bas ed on a single 1

- hour exposure of male Wistar rats to 26.7 9

mg/m 3 ; no deaths occurred during the 15

- day post

- exposure period (Livardjani et al. 1991). No 10

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

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

This 1

- hour highest non

- lethal value of 26.7 mg/m 3 meets the definition of the AEGL

- 3. The 13

26.7 mg/m 3 value was adjusted by a total uncertainty factor of 3 (an interspeci es uncertainty 14

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

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

behavioral changes were observed in male and female Wistar rats inhaling 17.2 mg/m 3 for 2 17

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

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

factor of 3 are supported b y the non

- lethal concentrations estimated in accidental exposures [up 20

to 15 mg/m 3 for 0.75 hours [Shelnitz et al. 1988; AIHA 2002)] and measured in occupational 21

settings [0.4

- 2.0 mg/m 3 (AIHA 2002)]. The resulting 1

- hour value of 8.9 mg/m 3 was time

- scaled 22

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

2001) . Because the 8

- hour time

- scaled value of 1.1 mg/m 3 appears low in comparison to 24

accidental non

- lethal exposures and is lower than some chronic occupationa l exposures, the 8

- 25

hour value was set equal to the 4

- hour value. 26

27

The calculated values are listed in the table below. 28

29

S 1

. Summary of AEGL Values for Mercury Vapor

Classification 10

- min 30

- min 1

- h 4

- h 8

- h Endpoint (Reference)

AEGL

B 1 a

(Nondisabling) Not

Recommended Not

Recommended Not

Recommended Not

Recommended Not

Recommended No odor or warning

properties

AEGL

B 2

(Disabling) 3 .1 mg/m 3

(0. 38 ppm) 2 .1 mg/m 3

(0. 26 ppm) 1.7 mg/m 3

(0. 2 1 ppm) 0.67 mg/m 3

(0. 08 ppm) 0. 33 mg/m 3

(0. 04 ppm) No fetal effects:

4 mg/m 3 , 2 hours/day,

10 d

– rat

(Morgan et al. 2002)

AEGL

B 3

(Lethal) 16 mg/m 3

(2.0 ppm) 11 mg/m 3

(1.3 ppm) 8.9 mg/m 3

(1.1 ppm) 2.2 mg/m 3

(0.27 ppm) 2.2 mg/m 3

(0.27 ppm) Highest non

- lethal

value, 26.7 mg/m 3 for

1 h

- rat

(Livardjani et al. 1991)

a Mercury vapor is odorless. AEGL

- 1 values are not recommended because mercury vapor has no odor or warning 30

properties at concentrations that may cause health effects

. 31

32

1. INTRODUCTION 33

34

Mercury vapor (CAS Reg. No. 7439

- 97

- 6) is a colorless and odorless gas generated from 35

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

vapor exist in the zero oxidation state (Hg o ). At ambient conditions, mercury is a silver

- white, 1

liquid metal. It is non

- flammable and on ly slightly volatile (vapor pressure of 0.002 mm). 2

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

2001; AIHA 200 2 ). Additional chemical and physical propert ies are summarized in Table 1. 4

5

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

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

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

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

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

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

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

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

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

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

16

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

cinnebar ore . World wide, c innebar is mined by open

- pit and underground mining; cinnebar is 18

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

a retort or furnace. Leaching, electrolysis, and electro

- oxidation methods have also been used

. 20

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

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

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

four major producing countries was 1300

- 1400 tons (DeVito and Brooks, 2005). 24

25

TABLE 1

. Chemical and Physical Properties

Parameter Value Reference

Synonyms Metallic mercury vapor;

elemental mercury v apor;

quicksilver (solid form) AIHA 200 2

Chemical formula Hg O = Neil et al. 2001

Molecular weight 200.59 O = Neil et al. 2001

CAS Reg. No. 7439

- 97

- 6 AIHA 200 2

Physical state Liquid metal; colorless vapor

generated from elemental liquid

mercury or inorgani c compounds of

mercury AIHA 200 2

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 200 2

Saturation concentration in air 13 mg/m 3 (1.6 ppm) at 20  C

16 mg/m 3 (2.0 ppm) a t 22  C

30 mg/m 3 3.7 ppm at 30  C

111 mg/m 3 (13.5 ppm) at 50  C AIHA 200 2

Liquid density (water =1) 13.5 g/cm 3 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 l imits Not flammable AIHA 200 2MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 9 of 51

Conversion factors * 1 ppm = 8.20 mg/m 3

1 mg/m 3 = 0.122 ppm AIHA 200 2

*In this document, values reported in ppm have been converted to mg/m 3 for consistency. 1

2

2. HUMAN TOXICITY DATA 3

4

Mercury vapor is odorless (ATSDR 1999). 5

6

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

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

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

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

15

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

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

13

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

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

concentrations, symptoms includ e tremor or increased excitabi lity. Chronic exposure can result 16

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

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

1996). I ncreased excitab ility, tremors, and gingivitis have been associated historically with 19

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

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

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

baby products , and s ensitive infants developed skin rash

. 23

24

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

(1972), U.S. EPA (199 5), ACGIH (1996), ATSDR (1999), AIHA (2002), and WHO (2003). 26

27

2.1. Acute Exposures 28

2.1.1. Lethality 29

30

Concentrations lethal to humans have been reconstructed from accidental exposures 31

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

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

(200 2 ) as follows. Eight employees were accidentally exposed during recovery of tons of warm 34

mercury spilled from a ruptured generat or (Ten n ant et al. 1961) . The exposure duration was 3

- 5 35

hours and the atmospheric concentrations were estimated at 18

- 30 mg/m 3 (2.2

- 3.7 ppm) based on 36

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

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

confined space to cut mercury

- contaminated pipes ( Eto et al. 1999; Kurisaki et al. 1999; Asano et 39

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

- 3 hours 40

for the three fatal ities and the concentration was estimated at 43 mg/m 3 (5.2 ppm) based on a 41

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

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

individuals became ill; the only fatality was an infant (Campbell 1948)

. According to the study 44MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 10 of 51

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

been rep orted when the infant was admitted to hospital. 2

3

2.1.2. Nonlethal Toxicity 4

5

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

metabolism studies (See Section 4.1 for metabolism studies). AIHA (200 2 ) d escribed two 7

instances in which exposures to estimated concentrations of 13 mg/m 3 (1.6 ppm) for 3

- 5 hours or 8

16 mg/m 3 (2 ppm) for <8 hours produced cough, dyspnea

, and chest tightness (Seaton and 9

Bishop 1978; McFarland and Reigel 1978). In a third report, high

- school

- age studen ts exposed 10

to an estimated 15 mg/m 3 (1.8 ppm) for 0.75 hours failed to exhibit signs of acute Hg 0 poisoning 11

(Shelnitz et al. 1988). Exposure of the students was verified by long

- term measurements of 12

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

no fatalities. The estimated concentration was 16 mg/m 3 and the duration was estimated a t a few 14

hours. 15

16

TABLE 2

. Estimated Human Exposures

- Reconstructions of Accidental Exposures a

Expo sure 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/m 3 (2.2

- 3.7 ppm) 8 (8, 1)

Torches used in confine d space

to cut contaminated pipes ( Eto

et al. 1999; Kurisaki et al.

1999; Asano et al. 2000) ) 2

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

Liquid mercury poured on

stove d (Campbell 1948) “ few h ” 16 mg/m 3 (2 ppm) 3 (3, 1 [infant])

Home gold ore processing d

( Hadda d and Stenberg 1963) “ few h ” 16 mg/m 3 (2 ppm) 2 (2, 0)

Home gold ore processing d

(Hallee 1969) “ few h ” 16 mg/m 3 (2 ppm) 5 (5, 0)

Workers exposed to vaporized

mercury in airflow e (Seaton and

Bishop 1978) 3

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

Broken thermosta t on hot oven

in small building (McFarland

and Reigel 1978) <8 h 44.3 mg/m 3 (5.4 ppm) c 9 (6, 0)

Mercuric oxide heated in

unventilated school laboratory d

(Shelnitz et al. 1988) 0.75 h 15 mg/m 3 (1.8 ppm) 23 (0, 0)

a Data taken from AIHA 200 2

. 17

b Symptoms su mmarized in text. 18

c AIHA (2002) reported an estimated concentration of 16 mg/m 3 (see footnote d). 19

d The minimum of the computed air concentration (mass of vaporized mercury divided by volume of enclosed area) 20

and the theoretical air saturation concentratio n for mercury vapor (16 mg/m 3 ) at the known or assumed air 21

temperature of 22oC. 22

e Mercury vaporized (estimated at 100 mL) at 90oC, blown into a pressure chamber at 500 ft 3 /min, temperature of 23

walls 260 oC, then into chamber (7.2 x 2.4 x 1.8 m) containing w orkers at 20oC. Twenty hours later, 2 mg/m 3 24

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

1

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

to mercury while repairing a mercury

- contaminated tank. Individual exposures depended on task 3

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

similar tank showed mercury concentrations of 1.1 to 2.9 mg/m 3 in the breathing zone of the 5

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

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

8

2.2. Occupational Monitoring 9

10

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

showed TWAs of metallic mercury vapor of 0.152 m g/m 3 (0.019 ppm) and 0.131 mg/m 3 12

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

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

0.190 mg/m 3 (0.023 ppm) for 8 hours. Stationary sampling in the room showed a TWA of 15

0.060 mg/m 3 (0.007 ppm). For an additional 7 workers, concentrations in work rooms were 16

between 0.010 and 0.400 mg/m 3 (0.001 and 0.049 ppm). Two of the workers (not clearly stated 17

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

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

20

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

occupations. Mean air concentrations r anged up to 0.20 mg/m 3 (0.024 ppm). IARC pointed out 22

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

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

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

symptoms such as slight objective changes in short

- term memory or tremor may occur with long

26

term exposure to mercury vapor at levels  20  g/m 3 (0.0024 ppm). 27

28

AIHA (200 2 ) summarized pa st workplace exposures. Concentrations in the range of 29

0.4

- 2 mg/m 3 (0.05

- 0.25 ppm) in industries have resulted in chronic mercury poisoning. Air 30

concentrations of 1.0

- 5.0 mg/m 3 (0.12

- 0.61 ppm) were not unusual in mercury mining operations 31

in the past. 32

33

2 .3. Neurotoxicity 34

35

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

(Goyer and Clarkson 2001). As noted, high, acute, non

- fatal concentrations produce tremor and 37

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

non

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

40

2.4. Developmental/Reproductive Toxicity 41

42

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

were sum marized by ACGIH (1996), ATSDR (1999), and AIHA (200 2 ). No numeric acute

44

duration exposure data were available . Retrospective studies on human fertility were evenly 45

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

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

- year 1

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

concentration, 0.09 mg/m 3 ; range, 0.025

- 0. 60 mg/m 3 ) did not reve al a significant difference from 3

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

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

statistically non

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

extrophy of the bladder was higher in Hg

- exposed workers than in unexposed workers (4.2% vs 7

0%). But, t here was no apparent concentration

- response relationship for the congenital 8

anomalies (conc entrations of 0.025 to 0.23 mg/m 3 ) ; however, the study authors noted the small 9

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

o r prospective epidemiological study, be conducted. Health habits of the pr egnant women were 11

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

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

14

According to AIHA (200 2 ), c ase studies of accidental exp osures suggest that infants and 15

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

lung injury

. M any of these studies did not cite concentrations. I n some cases, infants may have 17

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

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

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

household. 21

22

The concentration of total mercury in brain and kidney of 18

- 19 terminated fetuses and 23

14

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

in the brain of fetuses and infants w ere 5 and 6 μg/kg (ng/g) wet weight ( r ange, ≤2

- 23 μg/kg). 25

The me an concentrations in the kidney of fetuses and infants were 9 μg/kg (range, ≤5

- 34 μg/kg) 26

and 1 2 μg/kg (range, 3

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

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

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

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

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

similar to that found by Fredriksson et al. (1996) for rats exposed in utero to 1.8 mg/m 3 during 32

PND 2

- 3. 33

34

2.5. Genotoxicity 35

36

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

studies of occupationally

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

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

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

EPA 1995 ). 41

42

2.6. Carcinogenicity 43

44

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

EPA ( 1995 ). A CGIH used an A4 classification

- not classifiable as a human carcinogen

- for 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 13 of 51

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

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

inadequate and assigned a classification of D

- not classifiable as to human carcinogenicity

. The 3

U.S. EPA identified a LOAEL for systemic effects of 0.025 mg/m 3 (0.003 ppm) for chronic 4

(8

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

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

identified. 7

8

2.7. Summary 9

10

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

occupational monitoring. Concentrations from the reconstructed accidental exposures were 12

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

death, tissue concentrations at autopsy. Estimated exposures of 3

- 5 hours to 18

- 30 mg/m 3 (2.2

- 14

3.7 ppm) and 2

- 3 hours at 43 mg/m 3 (5.2 ppm) killed some workers (AIHA 200 2 ). E xposures to 15

c oncentrations of 13

- 16 mg/m 3 (1.6

- 2 ppm) for several hours caused cough, shortness of breath, 16

and chest tightness (Seaton and Bishop 1978; McFarland and Reigel 1978; AIHA 200 2 ). One 17

case report of expo sure to 15 mg/m 3 (1.8 ppm) for 0.75 hours found no overt symptoms (Shelnitz 18

et al. 1988). An estimated concentration of 16 mg/m 3 was not lethal to adults, but one infant died 19

following exposure of a “few hours.” 20

21

Occupational studies indicate that exposure to mercury vapor concentrations of 0.4

- 22

2 mg/m 3 (0.05

- 0.25 ppm) may induce symptoms of mercury intoxication but only after repeated 23

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

exposure to these concentrations for hours or days (AIHA 200 2 ). 25

26

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

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

significant relationship. Additionally, the A merican Industrial Hygiene Associa tion reported that 29

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

200 2 ). Mercury vapor does not appear to be genotoxic. S tudies are too limited to allow a 31

conclusion concerning its carcinogenic potential

. 32

33

3. ANIMAL TOXICITY DATA 34

3.1. Acute Studies 35

36

Acute studies with both lethal and non

- lethal endpoints are summarized in Table 3. 37

38

3.1.1. Rats 39

40

Groups of 32 male Wistar rats inhaled (whole

- body) analytically

- determined 41

concentrations of 26.7 mg/m 3 (3.25 ppm ) for one hour or 27.0 mg/m 3 (3.29 ppm) for two hours 42

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

to 26.7 mg/m 3 for one hour died and no clinical signs were evident. Animals inhaling 27.0 44

mg/m 3 for two hours showed dyspnea and 20 died within 5 days of exposure. Microscopic 45MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 14 of 51

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

fibrosis. 2

3

3.1.2. Mice 4

5

Groups of 16 C57Bl6 wild

- type and metallothionein

- null mice inhale d 0 or 5.5

- 6.7 mg/m 3 6

(0.67

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

post

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

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

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

within normal limits. 11

12

Twenty

- four male ICR mice inhaled an analytically

- determined concentration of 9.8 13

mg/m 3 (1 .2 ppm) mercury vapor for 1 hour ; groups of six animals were sacrificed at 1, 24, 48, 14

and 120 hours after exposure (Shimojo et al. 1996). Protein in broncho

- alveolar lavage fluid 15

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

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

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

. 18

S uperoxide dismutase, an antioxidant enzyme, increa sed following exposure, but returned to a 19

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

21

3.1.3. Rabbits 22

23

Rabbits were exposed to mercury vapor at an average analytically

- determined 24

concentration of 28.7 mg/m 3 (3.5 ppm) for 1 t o 30 hours (Ashe et al. 1953). Fourteen rabbits 25

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

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

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

damage to the brain, kidney, heart, and lung (not further described). A two

- hour exposure (2 29

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

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

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

destruction with widespread necrosis. One rabbit inhaling Hg 0 for 6 hou rs/day for 5 days (total 33

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

35MERCURY 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/m 3

(3.25)

27.0 mg/m 3

(3. 29) 1 h

2 h N o deaths; mild lung lesions;

no breathing difficulties

D eath of 20/32; severe lung

lesions; dyspnea Livardjani et al. 1991

Mouse 5.5

- 6.7 mg/m 3

(0.67

- 0.82) 3 h N ormal liver and kidney

function Yoshida et al. 1999a

Mouse 9.8 mg/m 3

(1.2) 1 h I ncreased protein content of

broncho

- alveolar lavage fluid Shimojo et al. 1996

Rabbit 28.7 mg/m 3

(3.5) 1 h

 4 h M ild organ damage

severe organ damage Ashe et al. 1953

1

3.2. Repeat

- Dose Studies 2

3

Recent repeat

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

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

included in Table 4. Data from repeat

- exposure studies that addressed neurotoxicity are 6

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

species and then by increasing concentration. Data from repeat

- exposure stud ies that addressed 8

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

10

Two dogs exposed 8 hours/day f or 40 days to 1.89 mg/m 3 (0.23 ppm) showed no clinical 11

signs (Fraser et al. 1934). Six dogs exposed 8 hours/day to 15.29 to 20.06 mg/m 3 ( 1.8 6

- 2.4 4 12

ppm ) died within 1

- 3 days and two of six dogs exposed daily for 8 hours to 12.55 mg/m 3 ( 1.5 3 13

ppm ) died withi n 2

- 3 days. The remaining dogs developed shortness of breath, weakness, 14

vomiting, and diarrhea. Although well

- conducted for the time, this study suffers from outdated 15

analytical methodology and the reported exposure concentrations are not reliable

. 16

17

Grou ps of 25 female Long

- Evans r ats were exposed nose

- only to 4 mg/m 3 (0.49 ppm) 2 18

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

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

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

no deaths were mentioned at sacrifice on day 37. 22

23

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

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

mg/m 3 (0.12 ppm) of mercury vapor for 24 hours/day, 7 days/week, for 5 weeks or 6 hours/day, 26

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

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

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

1992). 30

31

N o deaths occurred in a group of female Wistar rat s exposed to 1 mg/m 3 (0.12 ppm), 24 32

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

- state was 33

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

1

TABLE 4 . Summary of Rep eat

- Dose Inhalation Data in Laboratory Animals

Species Concentration

(ppm) Exposure

Duration Effect Reference

Rat, male

Wistar 0.48 mg/m 3 ( 0.06 ) 5 h/d, 4

- 5 d/wk,

8 wk “Irritable” behavior during

weeks 6

- 8; microscopic

changes in nervous system Schionni ng et al. 1998;

Sorensen et al. 2000

R at,

Norway 1 mg/m 3

(0.12) 24 h/d,

7 d/wk,

5 wks O ne death (of 7 rats) after 5

weeks of exposure Warfvinge et al. 1992

R at, female,

Wistar 1 mg/m 3

(0.12) 24 h/d,

28 d A ll rats survived; weight

loss; lethargy by the 7 th day;

slight tremors when handled

at termination Gage 1961

Rat, male,

(strain

unidentified) 3.0 mg/m 3 (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/m 3

(0.49) 2 h/d,

10 d No deaths, no kidney

damage Brambila et al. 2000

Rat, male and

female Wistar 17.2 mg/m 3 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/m 3

(0.007) 8 h/d,

23 wk Neurobehavioral effects

(increased activity) Yoshida et al. 2004

Mouse,

C57Bl6 0.1 mg/m 3

(0.12)

4.1 mg/m 3

(0.50) 1 h/d, 3 d/wk,

two w k,

fol lowed 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/m 3

(0.80

- 0.91) 4 h/d,

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

Rabbit, male 4.0 mg/m 3 (0.49) 6 h/d, 4 d/wk,

13 wk Slight tremors and clonus at

13 weeks Fukuda 1971

2

3

No deaths occurred and no signs of toxicity were evident in wild

- type or metallothionein

4

null mice exposed to 0.1 mg/m 3 (0.1 ppm) for 1 hour/day, 3 days/week for two weeks, followed 5

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

Metallothionein was induced/increased in the brains of wild

- type mice. Mercury could be 7

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

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

were observed in female OLA129/C57BL6 mice following exposure to 0.06 mg/m 3 for 8 10

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

- null 11

mice. 12

13

Groups of 14 C57Bl6 wild

- type and metallothionein

- null mice inhaled 0 or 6.6

- 7.5 mg/m 3 14

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

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

described. No wild

- type mice died over the 3

- day period. Two and eight metallothionein

- null 1

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

showed congestion, atelectasis

, and mild to m oderate hemorrhage in the alveoli of both wild

- type 3

and metallothionein

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

- null mice 4

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

exposure duratio n, metallothionein increased in the lung s of wild

- type mice, but not in the lungs 6

of metallothionein

- null mice. 7

8

A group of 16 rabbits inhaled 6.0 mg/m 3 (0.73 ppm) mercury vapor for 7 hours/day, 5 9

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

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

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

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

necrosis to nearly complete destruction with widespread necrosis. 14

15

3.3. Neurotoxicity 16

17

Neurotoxicity studies are discussed below. D evelopmental neurotoxicity studies are 18

summarized in Section 3.4 and Table 5. 19

20

Adult male Wistar rats inhaled 0.48 mg/m 3 of metallic mercury for 5 hours/day, 4 or 5 21

days/week over an 8

- week period (Schionning et al. 1998; Sorensen et al. 2000). During the last 22

2

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

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

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

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

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

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

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

volume of the granular cell layer. 30

31

Reversible behavioral changes were observed in male and female Wistar

- derived rats 32

exposed to 17.2 mg/m 3 (2.1 ppm) mercury vapor for 2 hours/day, 5 days /week for 18

- 22 33

exposures over 30 days (Beliles et al. 1968) and 14 male Wistar rats exposed to 3.0 mg/m 3 (0.37 34

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

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

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

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

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

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

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

tremor and some weight loss. The behavioral changes were reversed during a 60

- day recovery 42

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

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

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

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

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

measured with a vapor analyzer. 2

3

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

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

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

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

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

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

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

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

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

13

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

analytically determined average concentration of 4.0 mg/m 3 (0.49 ppm) mercury vapor for 6 15

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

the end of the weeks of exposure. 17

18

3.4. Developmental/Repro ductive Toxicity 19

20

Reproductive and d evelopmental toxicity studies including developmental neurotoxicity 21

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

23

Mercury vapor penetrates the maternal placental and blood

- br ain barrier of the developing 24

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

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

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

28

Pregnant squirrel monkeys were exposed to either 0.5 or 1.0 mg/m 3 (0.06 or 0.12 ppm) of 29

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

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

from 63

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

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

pregna ncies. The offspring were 0.8 to 4 years of age when evaluated in a lever

- press test. 34

Exposure

- related increases in performance variability and longer lever

- press duration were 35

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

among and between the controls and exposed groups. 37

38

Soderstrom et al (1995) exposed groups of eight pregnant Sprague

- Dawley rats to 1.5 39

mg/m 3 for 1 or 3 hours/day, either early in pregnancy ( gestation day [ GD ] 6

- 11) or late in 40

pregnanc y (GD 13

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

signs and development of the offspring observed at postnatal day 2

- 3 were normal. A group of 42

offspring were sacrificed on PND 2

- 3 for examination of mercury in differe nt areas of the brain. 43

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

nerve growth factor and its low

- and high

- affinity receptors (mRNA coding for nerve growth 45

factor) as well as choline acetyltransferase ac tivity. On day 2

- 3 postexposure, mercury 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 19 of 51

concentrations in brain of the neonate control and 1

- hour and 3

- hour exposure groups were 1, 4, 1

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

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

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

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

dama ge and disturbed trophic regulation during development. 6

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/m 3 2 h/d, 11

consecutive days;

(2) 1 or 2 mg/m 3 8 days

prior to and 8 days after

breeding (1) Estrous cycle and hormone level changes

secondary to general toxicity at 4 mg/m 3 ;

(2) No significant effect on pregnancy rate or

pregnancy maintenance Davis et al. 2001

Developmental/Neurotoxicity

Monkey 0.5, 1.0 mg/m 3

, 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/m 3

, 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 area s of the brain Söderstrom et al. 1995

Rat 1.8 mg/m 3

, 1 or 3 h/d

GD 11

- 14 or 17

- 20 No clinical signs and no effect on maturation

endp oints 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/m 3

, 1.5 h/d,

GD 14

- 19 No ef fect 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/m 3

, 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/m 3 (dams became moribund by PND 1);

decreased weight gain (7%) in the dams in

th e 4 mg/m 3 group Morgan et al. 2002 ;

Brambila et al. 2002

Rat 4 mg/m 3

, 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 0.0 5 mg/m 3

, 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

GD = gestation day. 9MERCURY 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/m 3 (0.2 2 ppm) mercury 3

vapor for 1 hour (defined as the low

- dose group) or 3 hours (high

- dose group) during GD 11

- 14 4

and 17

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

- 5

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

were analyzed for mercury. There were statistically significant dose

- related elevated amounts of 7

mercury in all organs analyzed except for brain in the low

- dose group. 8

9

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

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

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

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

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

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

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

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

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

groups of offspring. 19

20

Fredriksson et al. (1996) exposed 12 pregnant Sprague

- Dawley rats to 1.8 mg/m 3 (0.22 21

ppm) mercury vapor for 1.5 hours/day during GD 14

- 19. Additional groups were administered 22

methyl m ercury by gavage (2 mg/kg/day over GD 6

- 9) or both methyl mercury and mercury 23

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

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

negative geotaxis were unaffected within a few days after birth. When tested at 4

- 5 months of 26

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

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

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

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

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

vapor increased the mercury vapor

- induced deficits. 32

33

Pregnant Long

- Evans rats were exposed nose

- only to analytically

- determined 34

concentrations of 0, 1, 2, 4, or 8 mg/m 3 of mercury vapor for 2 hours/d ay from GD 6 through 15 35

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

1 week after the last exposure. Maternal toxicity, described as concentration

- related decreases in 37

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

glucose), were observed in rats exposed to 4 and 8 mg/m 3 . Dams exposed to 8 mg/m 3 exhibited 39

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

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

maternal lung, liver, or kidney of any rats exposed to 1, 2, 4, or 8 mg/m 3 at GD 6 or 15, or 42

PND 1. Metallothionein and glutathione S

- transferase activity levels were incre ased in the 43

kidney, lung, and brain of maternal animals (measured only in the 4 mg/m 3 group), but not in the 44

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

of concurrent control non

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

confined to the 8 mg/m 3 group and consisted of increased resorption, decreased litter size, and 1

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

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

exposure days and increasing exposure concentration. At the end of the 10

- day exposure, 4

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

transplacen tally

- exposed neonates of dams exposed to 4 mg/m 3 , mercury accumulation in the 6

kidney was approximately 1000

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

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

caused maternal toxicity. 9

10

The effect of mercury vapor exposure on neuronal function o f the above gestationally

11

exposed rats was reported by Herr et al. ( 2004). The study was limited to effects on offspring of 12

pregnant Long Evans rats exposed nose

- o nly to 0 or 4 mg/m 3 for 2 hours/day on GD 6 through 13

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

Offspring (one female and one male per dam) were tested between postnatal days 140

- 168 using 15

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

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

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

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

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

. 20

21

Fredriksson et al. (1992) exposed groups of 10 neonatal Sprague

- Dawley rats to an 22

analytically

- determ ined concentration of 0.05 mg/m 3 (0.006 ppm) for 1 hour (low exposure) or 4 23

hours (high exposure) daily from days 11

- 17 of age. This period of time is considered a period of 24

rapid brain growth in rats. Rats were tested for behavioral changes at 2

- 6 month s of age. Tests 25

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

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

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

and over the one

- hour observation time (broken into three 20

- minute sessions). At two months 29

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

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

activity and a decrease in rearing. At four months of age, the low

- dose rats showed increased 32

locomotion and total activity and decreased rearing; the high

- dose rats showed a marked 33

hyp oactivity in all three motor activity tests. In the radial

- arm maze, tested over 2 days at 6 34

months of age, rats showed a concentration

- dependent impairment in learning. Learning 35

improved over the two

- day test for the control and low

- exposure groups, but not for the high

36

exposure group. There was no difference among control and treated groups in the swim maze 37

test. 38

39

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

Sprague

- Dawley rats, nose

- only, to 0, 1, 2, or 4 mg/m 3 me rcury vapor for 2 hours/day for 11 41

consecutive days. A two

- hour exposure to 4 mg/m 3 for 11 days resulted in a 22% weight 42

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

respectively). Estrous cycles were slig htly prolonged in the 2 and 4 mg/m 3 dose groups, and 44

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

in the 4 mg/m 3 group compared to controls. These effects were attributed to body weight loss 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 22 of 51

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

mg/m 3 of mercury vapor, 2 hours/day for 8 days prior to breeding or 8 days after breeding. There 2

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

4

3.5. Genotoxicity 5

6

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

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

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

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

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

- related 11

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

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

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

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

mercury compounds have some genotoxic or clastogenic potential. 16

17

3.6. Chronic Toxicity/Carcinogenicity 18

19

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

d amage in 24 rats exposed to 0.1 mg/m 3 of mercury vapor for 7 hours/day, 5 days/week for 72 21

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

inadequate (U.S. EPA 1995 ). Their classification is D

- not classifiable as to human 23

carcinogenicity

. 24

25

3.7. Summary 26

27

Recently conducted studies show that a 1

- hour exposure of mice to 9.8 mg/m 3 mercury 28

vapor resulted in lung damage (Shimojo et al. 1996); whereas, a 2

- hour exposure of pregnant rats 29

to 8 mg/m 3 was a NOAEL for lesio ns of the lung, liver, and kidney when examined immediately 30

after exposure (Morgan et al. 2002). The 2

- hour exposure to 8 mg/m 3 resulted in a decreased 31

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

one

- hour exposure of rats to approximately 2 6.7 mg/m 3 resulted in lung lesions, but no deaths; a 33

2

- hour exposure to 27 mg/m 3 resulted in death of 20 of 32 rats (Livardjani et al. 1991). There 34

were no lesions of the lung, liver, or kidney in non

- pregnant and pregn ant female rats exposed to 35

4 mg/m 3 for 2 hours/day for 1 or 10 days (Brambila et al. 2002; Morgan et al. 2002). Kidney 36

lesions were not found in neonates exposed in utero to 4 mg/m 3 . Developmental effects were 37

observed only in association with maternal t oxicity, following repeated exposure to 8 mg/m 3

. 38

39

Reversible behavioral changes were observed in male and female Wistar

- derived rats 40

exposed to 17.2 mg/m 3 ( 2.1 ppm ) for 2 hours/day, 5 days/week for 22 exposures over 30 days 41

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

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

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

ki dney in the second study. 45

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

Developmental neurotoxicity tests with rats involving 6

- 8 daily 1

- 4

- hour exposures at 1

concentrations as low as 0.05 mg/m 3 ( 0.006 ppm ) were associated with altered spontaneous 2

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

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

provide sufficient information about the shape that a dose

- response relationship might assume, 5

and it did not ident ify a no

- effect level. 6

7

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

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

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

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

12

4. SPECIAL CONSIDERATIONS 13

4.1. Metabolism and Disposition 14

15

A review of animal and human studies indicates that 70

- 80% of in haled mercury is 16

absorbed into the lungs, primarily in the alveolar

- interstitial region (Leggett et al. 2001; AIHA 17

200 2 ). Deposition in the lungs is controlled by the rate of breathing (Hayes and Rothstein 1962). 18

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

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

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

- hydrogen 21

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

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

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

secreted in the bile. The presence of mercury in the body induces thiol

- containing proteins, the 25

metallothioneins. Induction of metallothioneins (regulated by at least two genes, MT

- 1 and MT

26

II) is believed to be a protective mechani sm. Metallothioneins are induced in the kidney and 27

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

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

30

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

where biotransformation takes place. Elemental mercury traverses the blood

- brain barrier more 32

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

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

related to exposure time and atmospheric concentration. Clearance half

- times of inhaled mercury 35

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

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

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

the expired air. 39

40

The biokinetics of inhaled mercur y vapor (Hg 0 ) have been studied in human subjects. 41

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

. 42

Exposure concentrations and durations ranged from 0.10 mg/m 3 (0.007 ppm) for 7 hours 43

(Teisinger and Fiserova

- Be rgerova 1965) to 0.40 mg/m 3 ( 0 .049 ppm) for 15 minutes (Sandborgh

44

Englund et al. 1998). No adverse effects were reported in these studies. The most recent, well

45

conducted study in which known extraneous sources of mercury were minimized is described. 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 24 of 51

Ad ditionally, a monitoring study is included in Table 7. B lood mercury in control subjects is 1

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

3

TABLE 6 . Human Metabolism Studies

Concentration

(Subjects) Exposure

Duration Observation Reference

0.050

- 0.35 mg/m 3

(3 male, 1 female

subjects) 5 min a 70

- 85% absorption Nielsen Kudsk 1965

0.06

- 0.11 mg/m 3

(5 male subjects) b 14

- 24 min 74% retention; 7% expired; tissue half

lives; lung, 1.7 days, head, 21 days Hursh et al. 1976;

Cherian et al. 1978

0.06

- 0.40 mg/m 3

(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/m 3

(9 males, females;

light physical

e xercise 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/m 3

(4 subjects); 0.20

mg/m 3 (1 subject) c 7 h 76% retention; urinary excretion

(  g/24 hours) approximated non

exposed values Teisinger and Fiserova

Bergerova 1965

0.01

- 0.106 mg/m 3 ;

mean 0.04 mg/m 3

(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 Exhaled air was collected for 5 minutes; it is assumed the exposures were also for 5 minutes. 4

b Subjects inhaled through a mouthpiece. 5

C Nasal inspiration and oral expiration. 6

7

8

Sandborgh

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

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

females, ages 19

- 53, inhaled 0.4 mg/m 3 (analytically determined range of 0.365 to 0.430 mg/m 3 ) 11

of mercury vapor through a reverse valve mouthpiece for 15 minutes. No ne of the subjects had 12

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

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

(range 57

- 73%). During the following three days, 7.5

- 12% of the absorbed dose was lost by 15

exhalation, with a median half

- life of mercury in expired breath of two days. Absorption by 16

blood and plasma was rapid, followed by a bi

- exponential decline in both media. S ubstantial 17

inter

- individual variat ion was observed in the area under the concentration

- time curves for blood 18

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

after exposure, and an estimated 8

- 40% was excreted during 30 days. Total mercury in b lood 20

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

- 7.6 21

nmol/L) to a maximum concentration of 7.4 nmol/L (median net value; 25

- 75 percentile of 6.6

- 22

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

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

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

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

Jonsson et al. (1999) used the data of Sandborgh

- Englund et al. (1998) to model the 1

kinetics of mercury vapor in humans. A four

- compartment model, including two depot 2

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

data. The median half

- time in the respiratory d epot compartment was estimated at 1.8 days; the 4

median half

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

6

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

high un quantified exposure to Hg vapor. Workers w ere also exposed to inorganic Hg 8

compounds and lead. Monitoring followed 2

- 10 days of exposure, 7 hours/day, after which signs 9

and symptoms of Hg intoxication appeared. The half

- life of the fast phase was 2

- 16 days and the 10

half

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

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

13

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

Monitoring was performed daily with personal samplers for 8

- hour period s for 5 days. 15

Atmospheric concentrations ranged from 0.010 to 0.106 mg/m 3 (overall mean 0.040 mg/m 3 ). 16

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

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

from graphs). 19

20

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

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

were 0.57 (0.50

- 0.70) mg/m 3 . Blood samples, taken at 4, 8, and 18 hours into the exposure, were 23

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

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

exposure (647

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

exposure of rats to a slightly higher concentration, 1.1 (0.55

- 1.72) mg/m 3 for 17 days, elimination 27

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

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

The authors stated that several rats died during the exposure to 1.1 mg/m 3 , but g ave neither the 30

number of rats nor day of death. 31

32

Neonatal rats were exposed to mercury vapor, 0.05 mg/m 3 for 1 or 4 hours/day, from days 33

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

(mg/kg) in t issue s of the control, 1

- hour, and 4

- hour exposure groups were: brain, 0.002, 0.002, 35

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

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

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

the occupational or diet sources (ATSDR 1999). 39

40

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

exposure groups ) (Halbach and Fichtner 19 9 3). Tissue concentrations

, determined immediately 42

after exposure

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

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

and 15 μg/kg, respectively. Following inhalation of 0.5, 1, or 2 mg/m 3 for one hour, brain 45

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

1

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

of high

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

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

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

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

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

. E xamples of 7

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

9

TABLE 7

. Tissue Concentrations of Mercury a

Concentration

(Subjects) Exposure

Duration Observation/Tissue Concentration Reference

Human Monitoring Studies

0.01

- 0.106 mg/m 3 ;

mean 0.04 mg/m 3 (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/m 3

(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 n g/g

Brain: 6 n g/g; kidney: 1 2 n g/g Lutz et al. 1996

Rodents

Rat: 4 mg/m 3

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 m g/m 3

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/m 3 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 μ g/g Fredriksson et al. 1992

Rat: 1.8 mg/m 3 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/m 3

Dam

Neonate 2 h/d, 4 days Brain:

Control: 29 ng/g

Exposed: 9 5 ng/g

Control: 19 ng/g

Exposed : 17 ng/g Yoshida et al. 1986

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

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

GD = gestation day; PND = post

- natal day. 2

3

In the study of Morgan et al. (200 2), metallothionein and mercury concentrations in 4

selected tissues of the dam and fetus were provided following inhalation of 4 mg/m 3 , 2 5

hours/day, on GD 6

- 15

. On GD 10, metallothionein concentrations were highest in the placenta 6

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

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

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

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

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

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

the concentration in the kidney of neonates exposed in utero to 4 mg/m 3 was 0.089 μg/g, whereas 13

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

15

Yoshida et al. (2002) studied the role of metalloth ionein in maternal

- to

- fetal distribution 16

of mercury in pregnant C57Bl6 mice. Following inhalation of 5.5

- 6.7 mg/m 3 for 3 hours during 17

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

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

maternal

- to

- fetal mercury transfer. In non

- exposed and mercury

- vapor exposed mice, 20

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

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

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

body) of exposed dams by a factor of 9

- 10 compared to fetuses of control dams. 24

25

During la te gestation, pregnant Hartley strain guinea pigs were exposed to 0.2

- 0.3 mg/m 3 26

for 2 hours/day for 4

- 11 days (Yoshida et al. 1986). Dams and offspring were sacrificed 27

immediately after birth. After 4 days of exposure, mercury in brain of offspring was n ot 28

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

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

31

Between GD 65 and 76, Hartley strain guinea pigs inhaled 8

- 10 mg/m 3 for 150 minutes 32

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

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

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

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

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

neonate brain concentrations were elevated 3

- to 5

- fold compared with current controls. On days 38

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

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

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

metallothionein (Yoshida et al. 1987). 42

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

4.2. Mechanism of Toxicity 1

2

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

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

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

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

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

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

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

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

11

4.3. Structure

- Activity Relationships 12

13

No data were located relevant to structure

- activity relationships

. 14

15

4.4. Other Relevant Information 16

4.4.1. Species Variability 17

18

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

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

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

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

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

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

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

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

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

at equivalent exposure concentrations

. 28

29

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

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

autopsy averaged 5 and 6 n g/g wet weight, respectively (ranges, 2

- 9 and ≤2

- 23 n g/g, respectively) 32

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

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

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

in the mothers. Mercury in control fetal guinea pigs and 5

- and 10

- day old guinea pigs averaged 36

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

exposure to 10 mg/m 3 of mercury for 150 minutes, brain concentrations in guinea pigs of the 38

respective age groups were 14±5, 27±1, and 32

- 33 n g/g wet weight. Fetal levels were measured 39

two hours post

- exposu r e. Th e mean concentrations of mercury in GD 15 fetuses of rat dams 40

exposed to 4 mg/m 3 mercury vapor for 10 days was 49 ng/g. Values could not be provided 41

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

repeat exposure. 43

44

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

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

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

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

3

4.4.2. Susceptible Populations 4

5

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

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

(ATSDR 1999 ; AIHA 200 2 ). Mercury (Hg o ) rapidly passes the blood

- brain barrier and reaches 8

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

neonatal rats involved repea t exposures (Fredriksson et al. 1992). Exposure to 0.0 5 mg/m 3 10

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

in some neurotoxicity tests but not in others. 12

13

Increased mercury uptake of neonates compared w ith dams may indicate increased 14

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

- hour

- old 15

neonates to 8

- 10 mg/m 3 of mercury vapor for 2 hours. Animals were sacrificed immediately 16

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

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

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

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

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

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

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

brain values of neonates being 12

- 28% higher. For both control and exposed groups, 24

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

26

In contrast to neonates, fetal tissues of rats accumulate less mercury than the tissues of 27

mercury

- treated dams (Fredriksson et al. 1992; Danielsson et al. 1993; Warfvinge et al. 1994; 28

Newland et al. 1996; Morgan et al. 2002). Following 10 days of exposure to 4 mg/m 3 , (GD 15) 29

total mercury in brains of dams and fetal rats were 3300 and 49 ng/g of tissue, respectively 30

(Morgan et al. 200 2 )

. 31

32

Following exposure of nine healthy male and female volunteers to 0.40 mg/m 3 for 15 33

minutes, the max imum blood concentration of mercury did not vary greatly (median, 7.4 nmol/L; 34

range, 5.9

- 13.0 nmol/L) (Sandborgh

- Englund et al. 1998). The time to maximum blood 35

concentration varied considerably. 36

37

Based on simulations of accidental exposure, a concentrati on of 16 mg/m 3 was fatal to an 38

infant (Campbell 1948), whereas concentrations of 18

- 43 mg/m 3 were fatal to 4 of 35 adults 39

(Tennant et al. 1961; Asano et al. 2000). 40

41

4.4.3. Concentration

- Exposure Duration Relationship 42

43

Studies with animal models show that t issue mercury concentration increases with 44

exposure concentration and exposure duration (Morgan et al. 2002; Yoshida et al. 1986). 45

However, no data were available to describe a concentration

- response relationship. Exponential 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 30 of 51

scaling (ten Berge et al. 19 86) was used to derive exposure duration

- specific values. It has been 1

shown that the concentration

- exposure time relationship for many irritant and systemically acting 2

vapors and gases may be described by C n x t = k, where the exponent n ranges from 0.8 t o 3.5. In 3

the absence of chemical

- specific data, an n value of 3 was applied to extrapolate to shorter time 4

periods, and an n value of 1 was applied to extrapolate to longer time periods to provide AEGL 5

values that would be protective of human health (NRC 2001). 6

7

4.4.4. Concurrent Exposure Issues 8

9

Amalgam dental fillings as well as food such as fish constitute major sources of chronic 10

mercury exposure in humans. Mercury vapor from amalgam dental fillings is a potentially 11

significant source of exposure to elemental mercury as estimates of daily intake from amalgam 12

restorations range from 3 to 17  g mercury/day, with the majority of individuals exposed to 5  g 13

mercury/day. Mercury in whole blood ranges from 2  g/L in the absence of fish consumption to 14

8  g /L when 2

- 4 fish meals/week are eaten. The mercury intake from fish is primarily in the 15

form of methyl mercury (Brune et al. 1991; Barregard 1993; Sandborgh

- Englund et al. 1998; 16

ATSDR 1999; WHO 2003). 17

18

Catalase inhibitors such as ethanol inhibit the oxid ation of elemental mercury to divalent 19

mercury, thus reducing mercury retention. Human subjects that ingested 65 mL of ethanol prior 20

to exposure to mercury vapor had reduced mercury retention, an increase in the rapid phase of 21

vapor loss by expiration, in creased mercury storage in the liver, a marked reduction in mercury 22

uptake by the red blood cells, and the abolition of prompt storage of mercury by the lung. 23

Similar results were seen with mice and rats (Hursh et al. 1980). 24

25

5. DATA ANALYSIS FOR AEGL

- 1 26

5 .1. Summary of Human Data Relevant to AEGL

- 1 27

28

Exposure to mercury vapor at low concentrations does not induce irritation or other 29

warning signs. There is no odor. 30

31

Controlled human exposures during metabolism studies used low concentrations and 32

short exp osure durations. No adverse effects were reported following exposure of healthy adults 33

to 0.10 mg/m 3 for seven hours (Teisinger and Fiserova

- Bergerova 1965) or 0.40 mg/m 3 for up to 34

15 minutes, the latter exposure accompanied by light physical exercise (Sa ndborgh

- Englund et al. 35

1998). 36

37

Under conditions of a reconstructed accidental exposure, high

- school

- age students 38

exposed to an estimated 15 mg/m 3 for 0.75 hours did not become ill (Shelnitz et al. 1988). 39

40

5.2. Summary of Animal Data Relevant to AEGL

- 1 41

42

Acu te studies with animal models used concentrations that induced effects greater than 43

those defined by an AEGL

- 1. Repeat

- dose studies, including neurotoxicity studies, resulted in 44

organ lesions; the time of appearance of these lesions could not be ascertain ed. 45

46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 31 of 51

5.3. Derivation of AEGL

- 1 Values 1

2

Mercury vapor is odorless and produces no irritation or early warning signs. Accidental 3

human exposures (Section 2.1) show that even lethal exposures may be tolerated for several 4

hours without apparent warning sign s. Because there are no signs of notable discomfort or 5

irritation at low concentrations, and studies that document asymptomatic, non

- sensory effects 6

that meet the definition of an AEGL

- 1 are not available, AEGL

- 1 values are not recommended 7

(Table 8 ). 8

9

TAB LE 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

6. DATA ANALYSIS FOR AEGL

- 2 11

6.1. Summary of Human Data Relevant to AEGL

- 2 12

13

As noted in Section 4 .1, no adverse effects were reported following controlled exposures 14

of healthy adults to 0.10 mg/m 3 mercury vapor for seven hours (Teisinger and Fiserova

15

Bergerova 1965) or 0.40 mg/m 3 for up to 15 minutes (Sandborgh

- Englund et al. 1998). The 16

latter exposure was accompanied by light physical exercise. 17

18

In their summary of occupational monitoring studies, the AIHA (200 2 ) notes that 19

exposure to mercury vapor concentrations of 0.4

- 2 mg/m 3 (0.05

- 0.25 ppm) A may result in 20

symptoms of mercury intoxica tion after exposures of weeks or longer. Adverse effects have not 21

been reported for exposure to these concentrations of hours or days. @ Similarly

, chronic exposure 22

to low concentrations during pregnancy (0.025

- 0.6 mg/m 3 ) have failed to show an increase i n 23

miscarriages or stillbirths, but congenital anomalies were non

- significantly increased (Elghany et 24

al. 1997). The increase was not concentration related. 25

26

Concentrations during accidental exposures are generally estimated. Students exposed to 27

an estima ted 15 mg/m 3 (1.8 ppm) in an unventilated high

- school lab for approximately 0.75 28

hours did not become ill (Shelnitz et al. 1988). Based on simulations of accidental exposure, a 29

concentration of 16 mg/m 3 for a “ few hours ” was fatal to an infant (Campbell 1 948) , whereas 30

concentrations of 18

- 43 mg/m 3 for several hours were fatal to 4 of 35 adults (Tennant et al. 1961; 31

Asano et al. 2000)

. 32

33

6.2. Summary of Animal Data Relevant to AEGL

- 2 34

35

Pregnant Long

- Evans rats exhibited no lesions of the lungs, liver, or kidn ey after 1, 5, or 36

10 two

- hour daily exposures to 4 mg/m 3 mercury vapor, although dams became moribund 37

following 10 days of exposure to 8 mg/m 3 (Brambila et al. 2002; Morgan et al. 2002). 38

Developmental effects consisting of increased resorptions and decrea sed litter size were confined 39

to the 8 mg/m 3 exposure group. No effects on pregnancy or offspring were reported in the group 40

exposed to 4 mg/m 3

. Following 10 days of exposure to 4 mg/m 3 , the mean mercury 41

concentration in the brain of the developing fetus was lower by 60

- fold than that in the brain of 42MERCURY 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/m 3 1

for 10 days was attributed to the repeat nature of the exposure. Pregnancies were uneventful in 2

squirrel m onke ys exposed to 0.5 or 1.0 mg/m 3 for approximately half of their gestation period, 3

but offspring tested at 0.8 to 4 years of age showed vari able behavioral deficits. 4

5

A 1

- hour exposure of mice to 9.8 mg/m 3 greatly increased the protein content of broncho

6

a lveolar lavage fluid; hemoglobin was present in the fluid at 48 hours, suggesting lung damage 7

(Shimojo et al. 1996). No deaths were reported within 5 days post

- exposure. Liver and kidney 8

function were normal in mice that inhaled 5.5

- 6.7 mg/m 3 for 3 hours as determined by sacrifices 9

up to 7 days later (Yoshida et al. 1999a). Rats exposed to 26.7 mg/m 3 for 1 hour showed no 10

breathing difficulties, but exhibited lung lesions (Livardjani et al. 1991). No deaths occurred 11

after the 1

- hour exposure ; but exten si on of the exposure for another hour resulted in 62.5% 12

mortality. 13

14

In repeat

- dose studies, reversible neurotoxicity was observed in rats exposed to 17.2 15

mg/m 3 mercury vapor for 2 hours/day, 5 days/week for 22 exposures (Beliles et al. 1968) or 3.0 16

mg/m 3 f or 3 hours/day, 5 days/week for 12 to 42 weeks (Kishi et al. 1978). Rats were held for up 17

to 12 weeks after cessation of exposure; only minor effects were reported. Developmental 18

studies with repeated exposures showed variable results and may not be rele vant to a single 19

exposure, as mercury accumulates in the brain with each successive exposure. 20

21

6.3. Derivation of AEGL

- 2 Values 22

23

Although maternal exposures were for 2 hours/day for 10 days, a single 2

- hour exposure 24

of pregnant Long

- Evens rats to 4 mg/m 3 m ercury vapor (Morgan et al. 2002) was used as the 25

point of departure for the AEGL

- 2. This value is a NOAEL for developmental effects. 26

Developmental effects including increased resorption, decreased litter size and decreased 27

neonatal weight were observed at the next highest concentration of 8 mg/m 3

. Uncertainty factors 28

for the AEGL

- 2 are based on a weight of evidence of approach. The following factors were 29

considered in deriving an interspecies uncertainty factor: the 4 mg/m 3 value was a NOAEL for 30

develo pmental effects (below the definition of the AEGL

- 2), the exposures were repeated for 10 31

days, rodents have a higher respiratory rate and cardiac output compared with humans ( resulting 32

in faster uptake )

, and human monitoring studies show some effects at co ncentrations of 0.4 to 2 33

mg/m 3 only with chronic exposure (AIHA 2002). The following factors were considered in 34

deriving an intraspecies uncertainty factor: the population of fetuses is considered a sensitive if 35

not the most sensitive population , the prot ective action of the placenta in sequestering mercury 36

[the mean concentration of mercury in the brain of dams exposed to 4 mg/m 3 for 10 days was 60

- 37

fold higher than in the fetal brain (Morgan et al. 2002)], and incidences of miscarriages and 38

stillbirths we re unaffected in women chronically exposed to 0.025 to 0.6 mg/m 3 , althoug h 39

anomalies were statistically n on

- significantly increased (Elghany et al. 1997). Based on these 40

factor s, interspecies and intraspecies uncertainty factor s of 1 and 3 were applied

. Application of 41

larger uncertainty factors, for example 10 or 30 (resulting in 2

- hour values of 0.4 or 0.13 mg/m 3 ), 42

results in values that are inconsistent with the available human data , including the chronic 43

exposure of pregnant women in the study of Elgha ny et al. (1997)

. In the absence of time

- scaling 44

information, t he resulting 2

- hour value of 1

. 3 3 mg/m 3 was time

- scaled using default n values of 3 45

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

- scaling 46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 33 of 51

calculations are in Appendix A and values are listed in Table 9 below. A category plot of AEGL 1

values in relation to toxicity data is shown in Appendix B. 2

3

TABLE 9

. AEGL

- 2 Values for Mercury Vapor

10

- min 30

- min 1

- h 4

- h 8

- h

3 .1 mg/m 3

( 0.38 ppm) 2

. 1 mg/m 3

( 0.26 ppm) 1.7 mg/m 3

( 0.21 ppm) 0.67 mg/m 3

( 0.08 ppm) 0. 33 mg/m 3

( 0.04 ppm)

4

The AEGL

- 2 values are supported by the data of Yoshida et al. (1986). Following 5

inhalation of 0.2

- 0.3 mg/m 3 , 2 hours/day for 4 days, by guinea pig dams, mercury concentrat ions 6

were elevated in the dam brain by a factor of 3.3 (95 vs 29 ng/g) whereas the concentration in the 7

neonate brain was similar to that of the control (19 and 17 ng/g , respectively ). 8

9

7. DATA ANALYSIS FOR AEGL

- 3 10

7.1. Summary of Human Data Relevant to AEG L

- 3 11

12

Human data are limited to reconstructions of accidental exposures. One such study 13

indicates that students exposed to an estimated 15 mg/m 3 in an unventilated high

- school lab for 14

approximately 0.75 hours did not become ill (Shelnitz et al. 1988). Lon ger exposures to similar 15

concentrations resulted in illness, and exposure to higher concentrations for several hours 16

resulted in some fatalities (see Table 2). 17

18

7.2. Summary of Animal Data Relevant to AEGL

- 3 19

20

Male Wistar rats inhaling 26.7 mg/m 3 mercury va por for one hour and observed for up to 21

15 days exhibited no clinical signs, but exhibited lung edema and necrosis (Livardjani et al. 22

1991). Extending the exposure period for another hour (at approximately the same 23

concentration) resulted in 62.5% mortali ty. Although the study is old, rabbits exposed to 31.3 24

mg/m 3 for 1 hour and held for 6 days showed no mortality , but mild to moderate undefined 25

changes in the lung, kidney, brain, and heart were observed (Ashe et al. 1953). 26

27

Reversible behavioral changes were observed in male and female Wistar

- derived rats 28

exposed to 17.2 mg/m 3 (2.1 ppm) for 2 hours/day, 5 days/week for 22 exposures over 30 days 29

(Beliles et al. 1968) and 14 male rats (strain unspecified) exposed to 3.0 mg/m 3 (0.37 ppm) for 3 30

hours/day, 5 d ays/week for 12 to 42 weeks (Kishi et al. 1978). Following a recovery period, 31

lesions were observed in the central nervous system in some rats in the first study and in the 32

kidney in the second study. 33

34

7.3. Derivation of AEGL

- 3 Values 35

36

The 1

- hour non

- leth al exposure of rats to 26.7 mg/m 3 (Livardjani et al. 1991) was used as 37

the point of departure for development of AEGL

- 3 values. The 26.7 mg/m 3 value was adjusted 38

by a total uncertainty factor of 3 (an interspecies uncertainty factor of 1 and an intraspeci es 39

uncertainty factor of 3) based on a weight of evidence approach. Larger uncertainty factors result 40

in values incompatib le with the overall data. Reversible behavioral changes were observed in 41

male and female Wistar rats inhaling 17.2 mg/m 3 for 2 hours /day for 22 exposures (Beliles et al. 42MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 34 of 51

1968). The uncertainty factor of 3 is considered sufficient to protect susceptible populations. 1

Values derived using an intraspecies uncertainty factor of 3 are supported by the non

- lethal 2

concentrations estimated in accidental exposures [up to 1 5 mg/m 3 for 0.75 hours [ Shelnitz et al. 3

1988; AIHA 200 2 )] and measured in occupational settings [0.4

- 2.0 mg/m 3 (AIHA 200 2 )]. The 4

resulting 1

- hour value of 8.9 mg/m 3 was time

- scaled using default n values of 3 and 1 for shorte r 5

and longer exposure durations, respectively. Because the 8

- hour time

- scaled v alue of 1.1 mg/m 3 6

appears low in comparison to accidental non

- lethal exposures and is lower than some chronic 7

occupational exposures , the 8

- hour value was set equal to the 4

- ho ur value. Time

- scaling 8

calculations are in Appendix A and values are listed in Table 10 below. A category plot of 9

AEGL values in relation to the animal toxicity and human metabolism data is found in Appendix 10

B

. 11

12

TABLE 10

. AEGL

- 3 V alues for Mercury Vapor

10

- min 30

- min 1

- h 4

- h 8

- h

16 mg/m 3

(2.0 ppm) 11 mg/m 3

(1.3 ppm) 8.9 mg/m 3

(1.1 ppm) 2.2 mg/m 3

(0.27 ppm) 2.2 mg/m 3

(0.27 ppm)

13

The derived values are supported by concentrations estimated during accidental non

14

lethal exposures. Concentrations of 15 mg/m 3 for 0.75 hours and 16 mg/m 3 for a “few hours” 15

were not lethal to older children and adults (although one infant death was recorded ) (AIHA 16

200 2 )

. The derived values are also supported by the study of Beliles et al. (1968) in whic h 17

reversible behavioral changes were observed in male and female Wistar

- derived rats exposed to 18

17.2 mg/m 3 mercury vapor for 2 hours/day, 5 days/week for 22 exposures over 30 days. A 19

histological change in the medulla oblongata comprised of perivascular c uffing by lymphocytes 20

was partially reversible following a recovery period. This lesion may be attributed to the repeat 21

exposure protocol. No lesions were observed in other tissues. 22

23

8. SUMMARY OF AEGLS 24

8.1. AEGL Values and Toxicity Endpoints 25

26

AEGL val ues are summarized in Table 1 1 . Because mercury vapor has no odor or 27

warning properties, AEGL

- 1 values were not recommended. 28

29

The point of departure for the AEGL

- 2 was a single 2

- hour exposure of pregnant rats to 4 30

mg/m 3 mercury vapor (Morgan et al. 200 2)

. The exposure to 4 mg/m 3 was a NOAEL for 31

developmental effects in rats. The 4 mg/m 3 value was adjusted by a total uncertainty factor of 3 32

(an interspecies uncertainty factor of 1 and an intraspecies uncertainty factor of 3) based on a 33

weight of eviden ce approach and the incompatibility of the derived values with monitoring data 34

if a larger uncertainty factor is used. Based on mercury uptake by the sensitive developing brain 35

of the fetus, compared with uptake by the brain of the dam, an intraspecies un certainty factor of 3 36

was considered sufficient to protect susceptible populations. In the absence of time

- scaling 37

information, the resulting 2

- hour value of 1.33 mg/m 3 was time

- scaled using default n values of 3 38

and 1 for shorter and longer exposure dura tions, respectively. 39

40

The point of departure for AEGL

- 3 values was the 1

- hour exposure of rats to 26.7 mg/m 3 41

(Livardjani et al. 1991). A 2

- hour exposure at this approximate concentration resulted in 42MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 35 of 51

significant mortality. The 26.7 mg/m 3 value was adjus ted by a total uncertainty factor of 3 (an 1

interspecies uncertainty factor of 1 and an intraspecies uncertainty factor of 3) based on (1) faster 2

uptake in rodents compared with humans and (2) the incompatibility with monitoring and 3

accidental exposure data if a larger uncertainty factor is used. The uncertainty factor of 3 is 4

considered sufficient to protect susceptible populations. The resulting 1

- hour value of 8.9 mg/m 3 5

was time

- scaled using default n values of 3 and 1 for shorter and longer exposure du rations, 6

respectively. 7

8

TABLE 11

. Summary of AEGL Values for Mercury Vapor

Classification Exposure Duration

10

- min 30

- min 1

- h 4

- h 8

- h

AEGL

- 1 a

(Nondisabling) Not

Recommended Not

Recommended Not

Recommended Not

Recommended Not

Re commended

AEGL

- 2

(Disabling) 3 .1 mg/m 3

(0. 38 ppm) 2.1 mg/m 3

(0. 26 ppm) 1

. 7 mg/m 3

(0. 21 ppm) 0.67 mg/m 3

(0. 08 ppm) 0. 33 mg/m 3

(0.0 4 ppm)

AEGL

- 3

(Lethal) 16 mg/m 3

(2.0 ppm) 11 mg/m 3

(1.3 ppm) 8.9 mg/m 3

(1.1 ppm) 2.2 mg/m 3

(0.27 ppm) 2.2 mg/m 3

(0.27 ppm)

a Mercury vapor is odorless. AEGL

- 1 values are not recommended because mercury vapor has no odor or warning 9

properties at concentrations that may cause extensive tissue damage. 10

11

12

8.2. Comparison with Other Standards and Guidelines 13

14

Standards and guidelines for exposure to mercury vapor are summarized in Table 1 2

. 15

The AIHA (200 2 ) did not develop an Emergency Response Planning Guideline

- 1 (ERPG

- 1) 16

because mercury vapor is odorless and produces no irritation or other early warning signs. The 17

ERPG

- 2 was based on a combination of animal studies (Fraser et al. 1934; Kishi et al. 1978; 18

Livardjani et al. 1991) and nine occupational studies. The occupational exposures involved 19

vapor concentrations of 0.05

- 0.25 ppm (0.41

- 2.1 mg/m 3 ) which resulted in symptoms in som e 20

workers after exposures of weeks or longer, but not after periods of hours or days. The ERPG

- 3 21

was also based on a combination of controlled laboratory studies with animals and fairly 22

consistent findings from accidental human exposures. 23

24

The 1

- hour Spac ecraft Maximum Allowable Concentration (SMAC) is 0.01 ppm 25

(0.08 mg/m 3 ) , and the 24

- hour value is 0.002 ppm (0.02 mg/m 3 ) (NRC 1996). The lung was 26

considered the target organ for acute exposure. The 1

- hour value was based on an estimated 27

LOAEL of 2 mg/m 3 f or 5 hours from reconstruction of accidental exposure of 13 workers. 28

Uncertainty factors of 10 and the square route of 13 divided by 10 were applied; the latter 29

number was applied to account for the small number of subjects. 30

31

The ACGIH ( 1996 ) TLV

- TWA of 0 .025 mg/m 3 was based on a combination of factors 32

including a Biological Exposure Index urine mercury level of 35  g Hg/g creatinine collected 33

prior to an 8

- hour work shift. The BEI applies only to exposure to elemental and inorganic forms 34

of mercury and n ot to organic mercury exposures. The monitoring data of Roels et al. (1987) 35

suggests that 50  g Hg/g creatinine is the biological threshold for neurological damage in 36

workers. 37

38MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 36 of 51

The NIOSH REL and the OSHA PEL are both 0.05 mg/m 3

, and the ceiling values 1

est ablished by NIOSH and OSHA are both 0.1 mg/m 3 . The NIOSH IDLH is 10 mg/m 3

. The 2

IDLH is based on acute inhalation toxicity data in animals in the study of Ashe et al. (1953). All 3

NIOSH and OSHA values have a skin notation. The German MAK is 0.1 mg/m 3 an d the Dutch 4

MAC is 0.05 mg/m 3

. 5

6

The National Academy of Sciences (NRC 1984) developed Emergency and Continuous 7

Exposure Limits (EEGLs) for Selected Airborne Contaminants. Their 24

- hour EE G L of 0.2 8

mg/m 3 was based on the data of Milne et al. (1970). In that study, four workmen became ill after 9

exposure to an estimated 1.1 to 4.0 mg/m 3 for 2.5 to 5 hours. A shorter

- term guideline was not 10

established. 11

12

TABLE 12

. Extant Standards and Guidelines for Mercury Vapor

Guideline Exposur e 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/m 3 2.1 mg/m 3 1.7 mg/m 3 0.67 mg/m 3 0.33 mg/m 3

AEGL

- 3 16 mg/m 3 11 mg/m 3 8.9 mg/m 3 2.2 mg/m 3 2.2 mg/m 3

ERPG

- 1 (AIHA ) a Not appropriate

ERPG

- 2 (AIHA) 0.25 ppm

(2.0 mg/m 3 )

ERPG

- 3 (AIHA) 0.5 ppm

(4.1 mg/m 3 )

SMAC (NRC) b 0.01 ppm

(0.08 mg/m 3 )

PEL

- ceiling

(OSHA) c 0.1 mg/m 3

IDLH (NIOSH) d 10 mg/m 3

REL

- TWA,

ceiling (NIOSH) e 0.05 mg/m 3

, 0.1 mg/m 3

TLV

- TWA

(ACGIH) f 0.025 mg/m 3

MAK

(Germany) g 0.1 mg/m 3

II(8)

MAC (The

Netherlands) h 0.05 mg/m 3

13

a ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 200 2 ) 14

The ERPG

- 1 is the maximum airborne concentra tion below which it is believed nearly all individuals could be 15

exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 16

perceiving a clearly defined objectionable odor. 17

The ERPG

- 2 is the maximum airbor ne concentration below which it is believed nearly all individuals could be 18

exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 19

symptoms that could impair an individual = s ability to take protecti ve action. 20

The ERPG

- 3 is the maximum airborne concentration below which it is believed nearly all individuals could be 21

exposed for up to one hour without experiencing or developing life

- threatening health effects. 22

23

b SMAC (Spacecraft Maximum Allowable Conce ntration, National Research Council) (NRC 1996) 24

SMACs are intended to provide guidance on chemical exposures during normal operations of spacecraft as well 25

as emergency situations. The one

- hour SMAC is a concentration of airborne substance that will not c ompromise 26MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 37 of 51

the performance of specific tasks by astronauts during emergency conditions or cause serious or permanent toxic 1

effects. Such exposures may cause reversible effects such as skin or eye irritation, but they are not expected to 2

impair judgment or interfere with proper responses to emergencies. 3

4

c OSHA PEL

- TWA (Occupational Safety and Health Administration, Permissible Exposure Limits

- Time 5

Weighted Average) (NIOSH 200 5 ) is defined analogous to the ACGIH

- TLV

- TWA, but is for exposures of no 6

more than 10 hours/day, 40 hours/week. 7

8

d IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) 9

(NIOSH 200 5 ) represents the maximum concentration from which one could escape within 30 minutes without 10

any escape

- impairi ng symptoms, or any irreversible health effects. 11

12

e NIOSH REL

- TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits

- 13

Time Weighted Average) (NIOSH 200 5 ) is defined analogous to the ACGIH

- TLV

- TWA. 14

15

f ACGIH TLV

- TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value

- 16

Time Weighted Average) (ACGIH 1996) is the time

- weighted average concentration for a normal 8

- hour 17

workday and a 40

- hour workweek, to which nearly all workers may be repeatedly expo sed, day after day, 18

without adverse effect. 19

20

g MAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche 21

Forschungsgemeinschaft [German Research Association] 2005) is defined analogous to the ACGIH

- TLV

- TWA. 22

For mercury, category II(8) indicates an excursion factor of 2, 8 times during the shift. 23

24

h MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 25

auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 20 00) 26

is defined analogous to the ACGIH

- TLV

- TWA. The 15

- minute peak is 0.5 mg/m 3

. 27

28

8.3. Data Adequacy and Research Needs 29

30

There are no human data with measured concentrations and symptoms that meet the 31

definitions of the AEGLs. Human metabolism studies use d relatively low and presumably safe 32

concentrations. The metabolism studies in conjunction with estimated concentrations from non

33

fatal human accidental exposures were considered in the development of AEGL values. An 34

AEGL

- 1 was not recommended because me rcury is odorless and without irritation at 35

concentrations that may be harmful. The AEGL

- 2 and AEGL

- 3 values were based on several 36

rodent studies that used suitable concentrations and exposure durations. The sensitive 37

developing fetus was considered in d evelopment of AEGL

- 2 values. 38

39

9. REFERENCES 40

41

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38MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 45 of 51

APPENDIX A: Derivation of AEGL Values 1

2

Derivation of AEGL

- 1 Values 3

4

Because mercury vapor has no odor or warning properties, AEGL

- 1 values are not recommended. 5

6MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 46 of 51

Derivation of AEGL

- 2 Values 1

2

Key Study: Morgan et al. 2002 3

4

Toxicity endpoint: A 2

- hour /day, 10

- day exposure to 4 mg/m 3 mercury vapor was a NOAEL for 5

increased resorptions and fetal death in pregnant rats. The next highe r 6

concentration , 8 mg/m 3 , resulted in fetotoxicity. 7

8

Time scaling: C n x t = k where n = 3 and 1 for shorter and longer exposure periods, 9

respectively (ten Berge et al. 1986; NRC 2001). 10

11

Uncertainty factors: Total of 3 (weight of evidence approach) 12

Interspecies: 1, based on the following factors: the 4 mg/m 3 value was a 13

NOAEL for developmental effects (below the definition of the AEGL

- 2), the 14

exposures were repeated for 10 days, rodents have a higher respiratory rate 15

and cardiac output compared with humans (resulting in faster uptake), and 16

human monitoring studies show so me effects at concentrations of 0.4 to 2 17

mg/m 3 only with chronic exposure. 18

Intraspecies: 3, based on the following factors: the population of fetuses is 19

considered a sensitive if not the most sensitive population, the protective 20

action of the placenta i n sequestering mercury (Morgan et al. 2002), and 21

incidences of miscarriages and stillbirths were unaffected in women 22

chronically exposed to 0.025 to 0.6 mg/m 3 , although anomalies were 23

statistically n on

- significantly increased. 24

25

Calculations: C/3 = ( 4 mg/m 3 )/3 = 1

. 33 mg/m 3 26

C 3 x t = k 27

( 1.33 ) 3 x 120 minutes = (2 82.32 mg/m 3 ) 3

 minutes 28

C 1 x t = k 29

1.33 x 120 minutes = 159.6 mg/m 3

 minutes 30

31

10

- minute AEGL

- 2: C 3 x 10 minutes = 2 82.32 (mg/m 3 ) 3

 minutes 32

C = 3.1 mg/m 3 33

34

30

- minute AEGL

- 2: C 3 x 30 minutes = 2 82.32 (mg/m 3 ) 3

 minutes 35

C = 2.1 mg/m 3 36

37

1

- hour AEGL

- 2: C 3 x 60 minutes = 2 82.32 (mg/m 3 ) 3

 minutes 38

C = 1.7 mg/m 3 39

40

4

- hour AEGL

- 2: C 1 x 240 minutes = 159.6 mg/m 3

 minutes 41

C = 0.67 mg/m 3 42

43

8

- hour AEGL

- 2: C 1 x 480 minutes

– 159.6 mg/m 3

 minutes 44

C = 0. 33 mg/m 3 45

46MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 47 of 51

Derivation of AEG L

- 3 Values 1

2

Key Study: Livardjani et al. 1991 3

4

Toxicity endpoint: Highest 1

- hour non

- lethal exposure of rats: 26.7 mg/m 3 5

6

Time scaling: C n x t = k where n = 3 and 1 for shorter and longer exposure periods, 7

respectively (ten Berge et al. 1986; NRC 2001). 8

9

Uncertainty factors: Total of 3 (an interspecies uncertainty factor of 1 and an intraspecies 10

uncertainty factor of 3), based on (1) faster uptake in rodents compared with 11

humans and (2) the incompatibility of derived values with monitoring data 12

and accide ntal exposure data if a larger uncertainty factor is used. The 13

intraspecies uncertainty factor of 3 is considered sufficient to protect 14

susceptible populations. 15

16

Calculations: C/3 = (26.7 mg/m 3 )/3 = 8.9 mg/m 3 17

C 3 x t = k 18

(8.9 mg/m 3 ) 3 x 60 minutes = (4229 8.14 mg/m 3 ) 3

 minutes 19

C 1 x t = k 20

8.9 mg/m 3 x 60 minutes = 534 mg/m 3

 minutes 21

22

10

- minute AEGL

- 3: C 3 x 10 minutes = 42298.14 (mg/m 3 ) 3

 minutes 23

C = 16 mg/m 3 24

25

30

- minute AEGL

- 3: C 3 x 30 minutes = 42298.14 (mg/m 3 ) 3

 minutes 26

C = 11 mg/m 3 27

28

1

- hour AEGL

- 3: C/3 = 8.9 m g/m 3 29

30

4

- hour AEGL

- 3: C 1 x 240 minutes = 534 mg/m 3

 minutes 31

C = 2.2 mg/m 3 32

33

8

- hour AEGL

- 3: C 1 x 480 minutes

- 534 mg/m 3

 minutes 34

C = 1.1 mg/m 3 (see below) 35

36

Because of inconsistency with some monitoring data and estimated non

- fatal concentrations, the 8

- hour 37

A EGL

- 3 value of 1.1 mg/m 3 was set equal to the 4

- hour value (2.2 mg/m 3 ). 38

39MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 48 of 51

APPENDIX B: Category Graph of AEGL Values and Toxicity Data 1

2

3

0.0 0.1 1.0 10.0 100.0mg/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

5MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 49 of 51

Data: 1

Category : 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal

Source Species mg/m 3 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 hum an 0.40 15 0 metabolism study

Teisinger and Fiserova

Bergerova 1965 human 0.10 420 0 metabolism study

Roels et al. 1987 human 0.04 480 0 occupational monitoring

Morgan et al. 200 2 rat 4.0 120 0 no fetotoxicity

Livardjani et al. 1991 ra t 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. 195 3 rabbit 28

. 7 60 2 mild organ damage

2

3MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 50 of 51

APPENDIX C : Derivation Summary 1

MERCU RY VAPOR (CAS Reg. No. 7439

- 97

- 6) 2

3

AEGL

- 1 VALUES

10

- min 30

- min 1

- h 4

- h 8

- h

Not

Recommended a Not

Recommended Not

Recommended Not

Recommended Not

Recommended

a AEGL

- 1 values are not recommended because mercury vapor has no odor or warning properties at concentrations 4

that may cause extensive tissue damage. 5

6

7

AEGL

- 2 VALUES

10

- min 30

- min 1

- h 4

- h 8

- h

3 .1 mg/m 3 2

. 1 mg/m 3 1

. 7 mg/m 3 0.67 mg/m 3 0. 33 mg/m 3

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/m 3 for 2 hours/day over GD 6

- 15

Effects: No fetotoxicity observed after 2 hour/day

, 10

- day exposure to 4 mg/m 3

. Developmental effects

including resorptions, decreased litter size and decreased PND 1 weight at 8 mg/m 3

. Endpoint/Concentration/Rationale: 2

- hour exposure to 4 mg/m 3 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/m 3 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 an d cardiac output compared with humans (resulting in faster uptake), and human monitoring

studies show some effects at concentrations of 0.4 to 2 mg/m 3 only with chronic exposure (AIHA 2002).

Intraspecies: 3, based on the following factors: the populati on 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/m 3 , 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: C n 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/m 3 ; range,

0.025

- 0.599 mg/m 3 ) did not reveal a significant difference from controls regarding miscarriages and

stillbirths, although congenital anomalies were statistically non

- significantly increased (Elghany et al. 1997)

.

8MERCURY VAPOR NAC/Proposed 2: 11/2009; Page 51 of 51

1

A EGL

- 3 VALUES

10

- min 30

- min 1

- h 4

- h 8

- h

16 mg/m 3 11 mg/m 3 8.9 mg/m 3 2.2 mg/m 3 2.2 mg/m 3

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 ra ts: 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/m 3 for 1 hour, 27.0 mg/m 3 for 2 hours

Effects:

1

- hour exposure to 26.7 mg/m 3 : no deaths over 15

- day observation period; lung lesions

2

- hour exposure to 27.0 mg/m 3 : death of 20/32 rats

Endpoint/Concentration/Rationale: NOAEL for lethality: 26.7 mg/m 3 for 1 hour meets the definition of the

AEGL

- 3

Uncertainty Factors/Rationale:

T otal 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: C n 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

- dos e 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/m 3

for 2 hours/day 5 days/week for 22 exposures showed behavioral changes that were reversible following a

recovery perio d. Organ lesions consisted of lymphocytic perivascular cuffing of the medulla oblongata.

2