P.1 

VII-41 

Table 7-11. Maximum Individual Blood Lead Levels for 99.5% of 

Children Under Different Air Lead Levels, Based on Mean PbB 

Predictions from CO Disaggregate Model (see Table 7-10) and Assuming 

Different Geometric Standard Deviations 

Predicted Geometric 

Air Lead Mean PbB Maximum PbB (ug/dl) 

(ug/m3) (ug/dl) GSD 

K 3 4 1.39 

0 4.42 9.4 10.3 

0.25 6.49 13.8 15.1 

0.50 8.51 18.1 19.9 

0.75 10.62 22.5 24.8 

1.0 12.69 26.9 29.6 

1.25 14.76 31.3 34.4 

^ 5 0 16.82 35 J 3JK2 

d) Summary of Predicted PbB Levels under Alternative Air Lead Levels 

Table 7-12 presents the various estimates of PbB levels for children 

(both mean and individual maximum for 99.5% of the population) under 

different average (monthly or quarterly) air lead levels based on the 

three modeling approaches discussed in this section and on the assumption 

that the population GSD is a constant between 1.34 and 1.39. It must be 

emphasized that for present purposes, each of the air lead levels are 

considered constant. In reality, if all areas are in attainment with a 

standard, air lead levels are generally below the standard so these results 

may be interpreted as conservative. Analyses are underway to better represent 

actual exposures in the future under alternative lead NAAQS. 

The ranges of PbB estimates under each air lead level reflect the 

differences among the available modeling approaches. Even within the 

individual approaches, there are ranges of estimates for both estimated 

mean PbB levels and estimated individual maximum PbB levels among 99.5% of 

the population. This reflects the uncertainty surrounding many of the 
Table 7-12. SUMMARY OF ESTIMATED BLOOD LEAD LEVELS UNDER DIFFERENT AIR LEAD LEVELS 

USING THREE MODELLING APPROACHES3 

Model 0.25 

Air Lead Level (tig/m3; monthly or quarterly average) 

0.5 0.75 1.0 1.25 1.5 

Integrated 

Uptake/ 

Biokineticb 

Urban/ 

Rural: 

Point 

Source: 

4.0-4.4 

(1.9) 

5.9-6.5 

(2.8) 

7.9-8.6 

(3.7) 

12.1-13.3 

(5.7) 

16.3-18.0 

(7.7) 

21.0-23.1 

(9.9) 

14.0-15.4 

(6.6) 

18.9-20.8 

(8.9) 

23.6-25.9 

(11.1) 

31.8-35.0 

(15.0) 

24.2-26.6 

(11.4) 

35.8-39.4 

(16.9) 

Aggregate 

Modelc 

11.5-18.9 

(5.4-8.1) 

13.6-22.4 

(6.4-9.6) 

15.7-25.9 

(7.4-11.1) 

17.8-29.4 

(8.4-12.6) 

20.0-32.9 

(9.4-14.1) 

22.1-36.4 

(10.4-15.6) 

Criteria Document 

Disaggregate Modeld 

13.8-15.1 

(6.49) 

18.1-19.9 

(8.51) 

22.5-24.8 

(10.62) 

26.9-29.6 

(12.69) 

31.3-34.4 

(14.76) 

35.7-39.2 

(16.82) ro 

aPbB levels are given in jjg/dl and represent the estimated levels (using specified GSDs) that 99.5% of children will not 

exceed for a given air lead level. Estimated population mean PbB levels are given in parentheses. 

bRange of PbB levels represent best estimates for individual children (2 years old) living in either general urban/rural 

areas or within 2-5 km of a lead point source and reflect range of GSDs used (1.34-1.39) to convert population mean PbB 

levels into 99.5% maximum individual levels. 

cRanqe of PbB levels reflects range of possible values for different parameters: Blood/air lead slope 

ug/m3); non-air PbB contribution (4.4-6.6 ng/dl); GSD (1.34 - 1.39). 

(4-6 yg/dl per 

dRange of PbB levels (for 2 year old children) reflects range of GSDs used (1.34 - 1.39) to convert population mean PbB 

levels into 99.5% maximum individual levels. 
P.3 

VII-43 

parameters used in the separate models, as well as actual variability in 

these parameters. For example, ranges of average absorption rates, hours 

spent outdoors, and soil and dust concentrations were necessary in the 

integrated uptake/biokinetic model to capture the physiological and behavioral 

variability among children and significant variability and uncertainty 

surrounding the relationship between air lead and soil/dust lead levels. 

In addition, the future impacts of the recent revisions to EPA's lead-in-gasoline 

phasedown schedule on atmospheric lead contributions to dietary lead consumption 

were necessary to project under alternative air lead levels. As discussed, 

the PbB estimates that are presented for the integrated uptake/biokinetic 

model for children living in general urban/rural areas and near point 

sources are the lower bound estimates from this model that are considered 

by the staff to be best estimates given the available data and the necessary 

assumptions used in the model. (Individual PbB levels that would not be 

exceeded for 99.5% of the population given different population mean PbB 

levels were calculated for the integrated uptake/biokinetic model using the 

same procedure (and the same GSD values of 1.34 to 1.39) presented previously 

in this section). Both epidemiological approaches, the aggregate and 

disaggregate models, rely on estimates of blood lead/air lead slopes, 

non-air PbB contributions, and GSDs, all of which contain ranges of interpretations. As in the integrated uptake/biokinetic model, these epidemiological models attempt to account for the contribution of air lead via all 

exposure pathways and to adjust non-air PbB contributions according to 

recent and future trends in various sources (e.g., canned food, paint lead). 

For each air lead level, the protection predicted by the three models 

is comparable. For example, the integrated lead uptake/biokinetic model 

estimates that, assuming a GSD between 1.34 and 1.39, an air lead level of 

0.75 ug/m3 would result in PbB levels no higher than 20.8 ug/dl among 
P.4 

VII-44 

2-year old children without excessive exposures to non-atmospheric lead 

(e.g., paint chips). Similarly, using the most conservative parameters in 

the "aggregated" blood/air lead slope model (i.e., blood/air lead slope of 

6, non-air lead of 6.6 yg/dl, GSD of 1.34), a 0.75 yg/m3 air lead level 

would protect 99.5% of children from exceeing 25.9 yg/dl, while using 

intermediately conservative parameters (i.e., blood/air lead slope of 5, 

non-air lead of 4.4, GSD of 1.34) results in a maximum PbB of 19.0 yg/dl. 

In comparison, the criteria document's estimates yield maximum individual 

PbB levels (for 99.5% of children) between 22.5 and 24.8 yg/dl for an air 

lead level of 0.75 yg/m3. 

It can be concluded that unless the least conservative parameter 

values are assumed in the aggregate epidemiological model (i.e., aggregate 

blood/air slope of 4, non-air PbB contribution of 4.4 yg/dl; see Table 

7-8 and 7-9), the models predict that if the current lead NAAQS level was 

just met so that the average air lead concentration was a constant 1.5 yg/m3, 

some fraction within the 99.5% of children would not be protected from 

exceeding 25 yg/dl, assuming a constant GSD between 1.34 and 1.39 for the 

entire distribution of blood lead levels. In fact, if 20 yg/dl is determined 

to be the maximum acceptable PbB for an individual child, regardless of which 

modeling approach is accepted, an air lead level no higher than 1.25 yg/m3 

would be required to protect 99.5% of the population, if that air lead level 

was constant and assuming the same "constant GSD" range. 

Should only one modeling approach be accepted as providing reliable 

estimates, these predictions would be revised accordingly. For example, if 

only the criteria document's disaggregate model is considered, assuming a 

constant GSD of 1.34 - 1.39, an air lead level no higher than 0.75 yg/m3 

would be required to protect 99.5% of children from exceeding 25 yg/dl, and 

no higher than 0.5 yg/m3 in order to protect against PbB levels above 

20 yg/dl. Roughly similar predictions for air lead levels of 0.5 to 0.75 
P.5 

VII-45 

ug/m3 that are just at attainment would be made using only the aggregate 

epidemiological model. However, the aggregate epidemiological model and the 

integrated uptake/biokinetic model predict that at higher air lead levels 

somewhat greater protection may be provided compared to the disaggregate 

model. For example, according to the uptake/biokinetic model a level possibly 

as high as 1.0 yg/m3 would be sufficient to protect children living near 

point sources from exceeding PbB levels of 25 yg/m3, and that 1.0 yg/m3 

may protect 99.5% of children living away from point sources from PbB levels 

above 20 yg/m3 if the air levels were just met, assuming a constant GSD 

between 1.34 and 1.39. If only the least conservative parameter values are 

assumed in the aggregate epidemiological model, an air lead level that is 

just attained at the current standard level of 1.5 yg/m3 may protect 99.5% 

of children from exceeding 25 yg/m3, while a level just attained at 1.25 yg/m3 

may be protective against PbB levels above 20 yg/m3. In order to protect 

against PbB levels above 15 yg/dl, an air lead level that is just attained 

at no higher than 0.5 yg/m3 would be required, regardless of which model is 

accepted, assuming GSDs in the range of 1.34 and 1.39. 

Finally, if the percentage of the population to be protected is changed 

from 99.5% to 99.0% or 99.9%, for example, or the GSD value that is used 

changes to 1.47 to reflect the overall value for a heterogeneous population 

the above calculations would be revised accordingly. 

e) Alternative Statistical Approach to Estimate Blood Lead Distributions • 

The three exposure models used in this section to predict the PbB levels 

associated with various air lead levels were designed to estimate mean blood 

lead levels of hypothetical populations given the available data and assumptions 

used in each of the models. In general, these models did not attempt to 

account for changes in PbB levels among children exposed to very high levels 
P.6 

VII-46 

of lead, typically from lead in paint. Given a population geometric mean 

PbB, the 99.5 percentile of each of the blood lead distributions for these 

populations was then calculated using geometric standard deviations (GSDs) 

derived from NHANES II in order to estimate the degree of protection against 

alternatively considered individual PbB levels determined to be associated 

with some health risk (i.e., 10 to 25 ug/dl). 

This approach has been questioned in that the distribution of PbB levels 

in children is really the sum of two distributions, one from general exposure 

to air lead, food lead, etc., and one from very high exposure to lead paint 

or other high concentration sources (Schwartz, 1985). Given that the sum 

of lognormal distributions is not lognormal, errors could be introduced by 

trying to fit a distribution at high levels using one overall GSD. Since 

one would not expect the PbB levels of highly exposed children to fall proportionately as the mean PbB level falls, the underestimate of the "fatness" 

of the tail would be expected to increase as the mean PbB level fell 

(Schwartz, 1985). 

This theoretical point is supported by the CDC and NCHS analysis of 

NHANES II data in which the sample was divided into two periods, before 

and after the increase in the rate of change of PbB levels (Annest et al., 

1983). For the second period, the GSD of both black and white children's 

PbB levels was approximately 1.43. However, the GSD that correctly predicted 

the percent of children above 30 ug/dl was 1.54, i.e., the extreme tail 

is fatter than predicted by the GSD that best fits the entire distribution. 

Moreover, the difference in these GSDs was larger in the second period, 

when mean PbB levels were lower than it was in the first period, 

indicating that the error increases as the mean PbB level falls (Schwartz, 

1985). Thus, it is possible that by using a constant GSD for an entire 
P.7 

VII-47 

distribution in setting a lead NAAQS, the number of children in the tail 

of the cumulative distribution function at high PbB levels would be underpredicted, and that the errors associated with estimating their PbB levels 

would change with the mean PbB level. 

An alternative approach that has been proposed relies on a logistic 

regression analysis of how the percentages of children in NHANES II who 

were above 15 ug/dl, 20 ug/dl, and 25 ug/dl varied with the mean of the log 

of children's blood leads for each study quarter (Schwartz, 1985). This 

approach makes no assumption about the shape of the distribution curve, but 

merely fits the tail area at the appropriate cutoff (e.g., 20 or 25 ug/dl) 

and thereby avoids the problem of using a constant GSD as well as incorporating 

the actual NHANES II data on children above those alternative target levels. 

The results are shown in Table 7-13. Using the results of this analysis, 

it is possible to calculate the mean PbB level that corresponds to a given 

choice of critical' lead level and a given fraction of the population to be 

held below that critical level. For example, if the critical level is 20 

ug/dl and the critical fraction is 99.5% of the children, the following 

equation is used: 

ln (p/l-p) = "15.506 + 5.246 mean ln (lead) 

for the 99.5% level, p = 0.005 and p/(l-p) = 0.005025 yielding 

-5.2933 = "15.506 + 5.246 mean ln (lead) 

which can be solved for the geometric mean PbB level. Table 7-14 compares 

estimated mean PbB levels using this regression analysis to those presented 

in Table 7-6 derived by using the range of constant GSDs presented in the 

CD and derived from NHANES II for each critical target PbB, assuming that 

99.5% protection is the goal. 

As discussed, the three modeling approaches presented earlier in 

this section estimated the population mean PbB levels predicted under 
Table 7-13. RESULTS OF LOGISTIC REGRESSION ANALYSIS OF NHANES II DATA 

Probability of 

being over: 

Coefficient 

Intercept/Mean Ln (Lead) 

Standard Error 

Intercept/Mean Ln (Lead) 

t-Statistic 

Intercept/Mean Ln (Lead) 

10 ug/dl 

15 pg/dl 

20 pg/dl 

25 pg/dl 

_a 

•13.418 / 4.998 

-15.506 / 5.242 

•16.202 / 5.053 

_a 

0.818 / 0.304 

1.123 / 0.409 

1.757 / 0.636 

_a 

9.22 / 7.94 

13.81 / 12.33 

16.40 / 16.44 

aGiven the limited sample size, a stable estimate could not be calculated. 

Source: Schwartz, 1985. 

Table 7-14. POPULATION MEAN BLOOD LEAD LEVELS (pg/dl) REQUIRED TO PREVENT 99.5% OF U.S. CHILDREN FROM 

EXCEEDING SPECIFIED BLOOD LEAD LEVELS ESTIMATED FROM ALTERNATE TECHNIQUES 

Maximum Acceptable Blood Lead Level (pg/dl) 

25 20 15 10 

i 

00 

Logistic Regression3 

Constant GSDC 

1.39 

1.34 

8.7 

10.7 

11.8 

7.0 

8.6 

9.4 

5.1 

6.4 

7.1 

_b 

4.3 

4.7 

aFrom results in Schwartz, 1985 based on analysis of NHANES II data. 

bGiven the limited sample size, a stable estimate could not be calculated. 

cDerived from analyses of homogenous populations sampled by NHANES II (CD, p. 11-30), 

00 
P.9 

VII-49 

various air lead levels, and the PbB levels at the 99.5 percentile were 

calculated for each mean PbB and assuming a constant GSD (either 1.34 or 

1.39) (See Table 7-12). For example, the criteria document "disaggregate" 

model estimates that at an average air lead level of 0.5 pg/m3, the 

population mean PbB level among children would be approximately 8.5 ug/dl 

which corresponds to keeping 99.5% of children from exceeding a PbB level 

of 18.1 or 19.9 ug/dl (depending on which GSD is assumed). In contrast, 

according to results of the Schwartz (1985) regression analysis, a population mean PbB level of 8.7 ug/dl would correspond to preventing 99.5% 

of children from exceeding a PbB level of 25 ug/dl. Obviously, significantly different impacts would be predicted under various air lead levels 

using either of these two statistical techniques to characterize the tail 

of a cumulative distribution of PbB levels while relying on the same three 

exposure models presented previously by this paper. Another illustration, 

using the aggregate epidemiological model, indicates that an air lead level 

of 0.75 pg/m3 would result in a population mean PbB level around 7.4 pg/dl, 

assuming blood/air lead slopes of 4 and a non-air PbB contribution of 4.4 

pg/dl. This mean PbB level corresponds to preventing 99.5% of children 

from exceeding either 15.7 or 17.3 pg/dl for GSDs of either 1.34 or 1.39, 

respectively. In contrast, according to the Schwartz (1985) regression 

analysis, a mean PbB level of 7.0 pg/dl would correspond to 99.5% of 

children from exceeding PbB levels above 20 pg/dl; i.e., an air lead level' 

of 0.75 pg/m3, using the same exposure model, would be significantly less 

protective based on the Schwartz (1985) analysis compared to the analysis 

using constant GSDs of 1.34 to 1.39. It appears that the proposed approach 

by Schwartz (1985), by more fully accounting for children in the tail end 

of the distribution, focuses on how those excessively exposed to sources 

of lead not affected by atmospheric emissions, such as paint lead, are 
P.10 

VII-50 

affected by incremental changes in air lead. Because of the significantly 

different predictions possible under these alternative approaches, the 

staff seeks CASAC guidance on the appropriate techniques for estimating the 

tail end of PbB distributions under alternative air lead levels and estimated 

population mean PbB levels. 

D. Summary of Staff Conclusions and Recommendations 

The major staff conclusions and recommendations made in Section VII, A-C 

are briefly summarized below: 

1) The quarterly averaging period used for the current lead standard 

allows significantly elevated monthly average concentrations, and repeated 

monthly excursions above a quarterly standard level may produce PbB levels 

elevated over those that would be predicted unless the standard was exceeded. 

Because such elevations may be associated with some increased health risk, 

the staff recommends that consideration be given to a monthly average 

since it would be more protective of children's health than the current 

quarterly standard. Guidance is requested from CASAC on whether the added 

protection provided by a change to a monthly standard would warrant a 

revision of the current quarterly averaging period. The staff also requests 

comment on whether the available information suggests the need for an 

averaging period less than a month. Should a monthly average lead NAAQS be 

chosen, it would be necessary to revise the current one in six day air lead 

sampling schedule. Analyses are underway to determine the most appropriate 

sampling schedules under a monthly standard. 

2) The primary lead NAAQS should be expressed in a statistical form 

rather than the current deterministic form. The decision on the statistical 

approach to be adopted, with possibly more frequent sampling, should be 

made in conjunction with establishing a level for the standard. 
P.11 

VI1-51 

3) Lead affects many different organ systems and biochemical/physiological 

processes across a wide range of exposure levels. These effects range 

from biochemical changes in energy metabolism, neurotransmission, and blood 

enzyme activity detectable at ^tery low dosages with no apparent threshold 

on a subcellular-molecular level, to severe, irreversible central nervous 

system damage manifested by mental retardation, encephalopathy and possibly 

death at PbB levels above 80-100 yg/dl. 

4) Based on recent studies, the PbB level of 30 yg/dl used as the maximum 

safe level for an individual child in setting the 1978 lead NAAQS contains 

little or no margin of safety for children from several adverse health 

effects. Based on an assessment of the available health effects data, the 

staff concludes that a child with a PbB of 25-30 yg/dl is at risk of significant alterations in heme synthesis (as indicated by elevated EP), depression 

in vitamin D metabolism, and possibly neurobehavioral disturbances, which 

collectively may represent impaired functioning and depleted reserve capacities 

of many different tissues and organs. Below 25-30 yg/dl, the risk associated with observed reductions in heme and vitamin D hormone synthesis, 

as well as altered brain wave activity and small decrements in cognitive 

function and behavior have not been fully determined. The CDC has revised 

the PbB level used to identify children with excessive lead exposure in the 

lead poisoning prevention screening program from 30 to 25 yg/dl, a medical 

"intervention" level that represents a compromise between the amount of 

tolerable risk and the practical limits of effectively implementing the 

existing screening program. The staff concludes that a PbB for an individual 

child of 25 yg/dl appears to contain little or no margin of safety from 

significant risks of multi-organ impairments and possible neurological 

dysfunction. 
P.12 

VII-52 

5) Fairly consistent results were provided by the three modeling 

approaches used to estimate PbB levels among children under alternative air 

lead concentrations assumed to be maintained at constant levels: the integrated 

lead uptake/biokinetic model, the aggregate epidemiological blood lead/air 

lead slope approach, and the disaggregate epidemiological approach presented 

in the criteria document. Calculations were performed on the assumption 

that the geometric standard deviation (GSD) for the child population is 

constant and in the range of 1.34 to 1.39 as cited in the CD. Based on 

this premise, all three models predicted that in order to prevent 99.5% 

of children from exceeding 25 pg/dl, an air lead level constantly at 

attainment, no higher than the current standard level would be required, 

and possibly no higher than 0.75 pg/m3, depending on the assumptions and 

calculations used in the different models. Should a PbB of 20 pg/dl be 

determined to be the maximum acceptable safe PbB level and assuming a goal 

of 99.5% protection, GSDs between 1.34 and 1.39, and an air level that is 

constantly maintained, then a level no higher than 0.5-0.75 pg/m3 would be 

required - unless the least conservative aggregate epidemiological model 

alone is considered, in which case, a level of 1.25 pg/m3 may be sufficient. 

A level that is maintained at 0.5 pg/m3, and possibly as low as 0.25 pg/m3, 

would be required to prevent 99.5% of children from exceeding PbB levels 

above 15 pg/dl, depending on which model is considered, and assuming a 

constant GSD between 1.34 and 1.39. 

Calculations were also performed based on a different characterization 

of the tail end of the distribution of children's PbB levels. This 

alternative statistical approach indicates that somewhat different average 

air lead levels would be required for equivalent health protection using 

the same three exposure modeling approaches. For example, the criteria 
P.13 

VII-53 

document "disaggregate" model estimates that at an average air lead level 

of 0.5 pg/m3, the population mean PbB level among children would be 

approximately 8.5 ug/dl which corresponds to keeping 99.5% of children from 

exceeding a PbB level of 18.1 or 19.9 pg/dl (depending on which GSD is 

assumed). In contrast, according to results using the alternative statistical 

approach (which is based on a logistic regression analysis of NHANES II data), 

a population mean PbB level of 8.7 pg/dl would correspond to preventing 

99.5% of children from exceeding a PbB level of 25 pg/dl. 

Further information and CASAC guidance is sought on: a) whether these 

modeling approaches are valid given the available data and how they can be 

improved; b) appropriate values of specific parameters within the various 

models, e.g., blood/air lead slope, non-air PbB contribution; and c) the 

appropriate statistical technique to characterize the tail end of the blood 

lead distribution under alternative air lead levels as predicted by the 

various models, i.e., should a "constant" GSD be used to represent the 

entire distribution of children's blood lead levels (and if so, what the 

appropriate GSD value is), or whether the alternative approach based on 

logistic regression analysis of NHANES II data would be an improvement. 
P.14 

VIII. CRITICAL ELEMENTS IN THE REVIEW OF THE SECONDARY STANDARD 

This section includes a discussion of information drawn from the 

criteria document that appears most relevant to the review and possible 

revision of the current secondary NAAQS for lead. It focuses on field 

and laboratory studies that identify potential effects of lead in biota 

of terrestrial and aquatic ecosystems at levels of exposure relevant to 

natural habitats. Within each category, the section presents 1) a 

brief summary of the relevant scientific information; 2) an evaluation of 

the potential quantitative relationships between lead and effects; and 3) 

an evaluation of the quantitative relationships between levels of lead 

in the natural habitat and biologically available lead. A preliminary 

staff recommendation is also presented, recognizing the major uncertainties 

in the available data, that consideration be given to making the secondary 

standard equivalent to the primary standard in all respects. 

I . Terrestrial Ecosystems 

Anthropogenic emissions of lead deposit on terrestrial ecosystems via 

wet and dry deposition. After initial deposition on vegetation and other 

surfaces, the migration and distribution of lead in the soil reservoir 

depend on a number of environmental factors that influence the immobilization 

of lead via precipitation, surface adsorption and ion exchange reactions 

(Zimdahl and Skogerboe, 1977; Miller & McFee, 1983; Camerlynck & Kiekens, 

1982). Once in the soil reservoir, lead is relatively insoluble and 

immobile (NAS, 1980; Nriagu, 1978) and is not readily removed by such 

mechanisms as leaching and stream run-off (CD, p. 8-7, 8-13). As a result, 

lead accumulates in the soil reservoir even when the deposition rate is 

relatively low. 
P.15 

VIII-2 

A. Mobility and Bioavailability of Lead 

Zimdahl and Skogerboe (1977) identified soil pH and cation exchange 

capacity (CEC) as primary determinants of a soil's capacity to bind lead. 

Based on their empirically derived equation, the binding capacity for 

lead for various soil types was estimated. Although the reliability of 

this equation to predict soil binding capacity is questionable (due to its 

linear form which may not be appropriate for high CEC's), this analysis 

suggests that while the capacity of certain soils to immobilize lead is 

large, it is finite. 

When examining the potential impact of lead on terrestrial ecosystems, 

a distinction must be made between total soil lead content and the available 

or potentially available fractions. The fraction of soil lead that may be 

biologically available includes the potentially available lead (exchangeable 

forms determined by chemical extraction) and the actually available water 

soluble forms (lead in soil moisture) (CD, p. 6-29). The generally low 

solubility of lead and the apparently small percentage (1-12%) of total 

soil lead that is exchangeable (Camerlynck and Kiekens, 1982; Miller and 

McFee, 1983; Hughes, 1981; Atkins et al., 1982) suggest that the bioavailability of this pollutant is quite limited. The potential effect of acid 

precipitation to increase the relative mobility of lead in soil (Tyler, 

1978; Hutchinson, 1980) is of clear concern as a mechanism that may increase 

the bioavailability of this heavy metal. 

Given the varying capacity of different soil types to immobilize lead 

under different environmental conditions and the limited usefulness of chemical 

extraction studies to provide reliable estimates of exchangeable soil lead 

fractions, it is difficult to predict the percentage of total soil lead that 

is biologically available (actual or potential). As a result, it is difficult 

to predict the magnitude of increase in total soil lead concentration that 
P.16 

VIII-3 

results in a soil moisture lead concentration associated with levels of 

biologically available lead that may cause adverse effects. 

B. Effects in Terrestrial Biota 

This section, based on the scientific literature summarized in 

the criteria document, includes a review of the effect of lead in 

components of the terrestrial ecosystem, i.e., flora, microbes and fauna. 

The lowest levels of exposure at which effects have been observed in 

field and laboratory studies are emphasized. The biological or ecological 

significance of certain lead-induced effects is unclear. This is primarily 

due to the difficulty in determining the long-term significance of subtle 

changes in ecosystem structure and function. Given the available data, it 

is difficult to assess the extent to which lead-induced effects constitute 

short or long-term, adverse environmental impacts. 

1. Flora 

a. Exposure, Uptake and Translocation 

Plant exposure to lead occurs via root uptake from the nutrient 

medium (soil moisture) (CD, p. 8-14). Although 90% or more of lead taken 

up via the roots may remain tightly bound in the roots (Koeppe, 1981), 

field and laboratory studies provide evidence that some lead is translocated 

to physiologically active tissues in vascular plants (CD, p. 8-15 to 8-17). 

Recent isotopic and mass balance studies suggest the mechanism of 

foliar uptake as another route of exposure of plants to lead (Facchetti 

and Geiss, 1982; Lindberg and Harriss, 1981). While the relative significance of foliar uptake has not been clearly determined, it is potentially 

quite high since surface deposition of lead is estimated to account for 

90% of total plant lead (CD, p. 8-38). Elevated lead burdens in plants 

near smelters and along roadsides, for example, have been attributed 
P.17 

VIII-4 

primarily to surface deposition (Getz et al., 1977; Nriagu, 1978; Smith, 

1976). Taken together, these studies suggest that deposition on vegetative 

surfaces and foliar uptake may be of greater importance than previously 

thought. 

b. Experimental Data from Hydroponically Grown Plants 

Experimental data on lead-induced effects in plants are available 

primarily from laboratory studies of agricultural plants grown in artificial 

nutrient media (i.e., hydroponic solution). These studies (Table 8-1) 

report that at relatively low concentrations, ranging from 2-10 pg Pb/g 

solution, inhibition of photosynthesis, alteration in enzyme activity 

and reduction in growth can occur. While the physiological and biochemical 

changes observed in these studies are biologically significant, the 

results cannot be readily extrapolated to the varied conditions present 

in natural habitats. Such factors as length of treatment (exposure), 

chemical form of lead, level of nutrients in solution, and age and species 

of plant can influence the experimental results (Koeppe, 1981; Paivoke, 

1979) and limit the extrapolation of controlled experimental results to 

the natural habitat. The absence of data to clearly define the quantitative 

relationship between soil moisture lead and total soil lead further limits 

the usefulness of laboratory studies of hydroponically grown plants for 

environmental impact prediction. Due to the absence of data, it is difficult 

to accurately assess the potential effect of lead in terrestrial flora. Leadinduced effects have been evaluated for a limited number of plant processes 

(CD, p. 8-17) and the data base on effects in non-agricultural plants and 

trees (Smith, 1981) is inadequate. 

c. Experimental Data of Plants Grown in Lead-Amended Soils 

Studies involving the artificial addition of lead salts to soil have 

evaluated lead-induced changes in plants at specified soil lead concentrations, 
Table 8-1. LEAD-INDUCED EFFECTS IN HYDROPONICALLY GROWN VASCULAR PLANTS 

Effect Species Lead concentration 

(pg Pb/g solution) 

Species of 

Lead Salt 

Length of 

Treatment 

Reference 

Inhibition of 

germinating root 

elongation 

50% reduction 

root growth 

Rye grass seedlings < 2.5 

1.7 

Lead nitrate 14 days Wong and Bradshaw 

(1982) 

Absence of root 

growth 

Inhibition of carbon 

fixation pathway 

Reduction in elongation 

Tomato chloroplasts 

Wheat seedlings 

5 

10.35 

10 

Lead nitrate 

Lead chloride 

Lead nitrate 

-

48 hours 

Miles et al. (1972) 

Lane et al. (1978) 

Inhibition of ATP 

content 

Kidney bean seedling 

leaves 

10 Lead nitrate 15 days Sung and Yang (1979) 

Buckwheat seedling 

leaves 

i 

Reduction in synthesis 

chlorophyll-a 

chlorophyll-b ' 

Oat seeds 10 Lead chloride 72 hours Hampp and Lendzian 

(1974) 

60% increase in acid 

phosphatase at 6 days, 

followed by decrease at 

12 days 

Inhibition of root growth 

Pea seedlings 

Inhibition of root growth Barley seedlings 

Lead acetate 12 days 

Lead chloride 12 days 

Lead nitrate 10 days 

Paivoke (1979) 

Garland and Wilkins 

(1981) 
P.19 

VIII-6 

In general, high concentrations of total soil lead are necessary before 

physiological effects in plants are observed. Khan and Frankland (1983) 

report significant growth reduction in radish plants with exposure to 

1000 pg Pb/g soil and complete growth inhibition at 5000 pg Pb/g soil. 

These total soil lead concentrations are found in certain high lead 

environments, i.e., near roadsides and smelters (Wheeler and Rolfe, 1979; 

CD, p. 7-30; Atkins et al., 1982). It is unclear, however, whether 

lead-induced effects would occur under natural soil conditions where the 

availability of lead is influenced by nutrient levels, organic matter 

content, CEC, and pH of the soil (Koeppe, 1981). 

d. Field Evidence of Lead-Tolerance 

Further indication of the effect of lead is provided by the 

identification of lead tolerant plant communities near roadsides and point 

source emissions (CD, p. 8-38; Antonovics et al., 1971; Atkins et al., 

1982). Potential changes in species composition in these areas have 

implications for the long-term effect of lead on ecosystem function and 

stability. At relatively low total soil lead concentrations (112 pg Pb/g 

soil), Atkins et al. (1982) suggest that selection pressure due to soil 

lead resulted in the evolution of lead tolerance in a roadside grass. 

2. Microbes 

Available data suggest that the impact of lead in terrestrial ecosystems may be evident first in the components of the soil and litter 

microcosm (e.g., fungi, bacteria and algae) (Tyler, 1972) that play a 

critical role in the decomposition of organic matter and in nutrient 

cycling (Doelman and Haanstra, 1979a; Doelman, 1978). 

a. Experimental Studies of Lead-Induced Effects 

Experimental studies provide evidence of lead-induced effects in 
P.20 

VIII-7 

soil microbes at soil lead concentrations as low as 750-5000 pg Pb/g 

soil (Table 8-2). In the presence of lead (1500 pg Pb/g soil), the 

composition of microbe communities may shift to more lead-tolerant 

populations (Doelman and Haanstra, 1979b) and, at soil lead concentrations 

found near roadways and point sources (750-2000 pg Pb/g soil), soil 

microbial activity may be sufficiently reduced to inhibit the decomposition 

and nitrification processes (Smith, 1981; Doelman and Haanstra, 1979a; 

Liang and Tabatabai, 1978). Inhibition of growth and activity in soil 

microbes has occurred at lead concentrations in solution of 10-50 pg Pb/ml 

(Table 8-2). 

While these data suggest that certain soil microbes can be affected by 

lead at soil lead concentrations found near roadsides and point sources, 

the data are inadequate to draw any general conclusions about the tolerance 

of soil microbes to lead (Doelman, 1978) and lead's effect on this 

ecosystem component as a whole. The inhibitory effect of lead appears to 

vary with different types of microbes (Johnson et al., 1982; Martin and 

Coughtrey, 1981). In addition, because microbes exhibit a diversity of 

functions that interact in ways that are not well defined (Swift et al., 

1979; CD, 8-22, 8-23), a broader data base, encompassing various taxonomic 

groups, is required for environmental impact prediction. Even drawing 

quantitative conclusions about the microbes studied in these experiments 

is constrained by experimental conditions that influence the bioavailability 

of lead and result in uncertainties associated with extrapolating laboratory 

results to the natural habitat. The long-term significance of lead-induced 

changes in soil microbial populations is unclear and depends on whether 

the ecosystem has the ability to compensate for such perturbations. 

The critical role of soil microbes in terrestrial ecosystem processes 
Table 8-2. EXPERIMENTAL EVIDENCE OF LEAD-INDUCED EFFECTS RELATING TO SOIL MICROBIAL ACTIVITY 

Effect Microbe Lead Concentration Reference 

Possible inhibition of 

decomposition 

Bacteria 2000 - 5000 pg Pb/g soil Smith (1981 ) a 

Delay and inhibition of decomposition of organic compounds 

Bacteria 750 - 1500 pg Pb/g soil 

Lead chloride 

Doelman and Haanstra 

(1979a) 

14% inhibition of nitrification Bacteria 1000 pg Pb/g soil 

Lead acetate 

Liang and Tabatabai (1978) 

Change in composition of microflora after 3 years (Selection 

of tolerant strains) 

Bacteria 1500 pg Pb/g soil 

Lead chloride 

Doelman and Haanstra (1979b) ' 00 

Inhibition in 50% of microbial 

strains 

Fungi 

Bacteria 

Actinomycetes 

50 pg Pb/mlb 

Lead acetate 

Williams et al. (1977c) 

Inhibition of growth Fungi 10-50 pg Pb/mlb 

Lead nitrate 

Babich and Stotzky (1979) 

aAs cited in Criteria Document, p. 8-22 

bNote lead concentration in solution 

ho 
P.22 

VIII-9 

(decomposition and nutrient cycling) suggests, however, the serious nature 

of the potential inhibition of microbial activity by lead and indicates 

the need for additional research to more clearly define the effect of 

lead in this ecosystem component. 

b. Field Evidence of Altered Microbial Activity 

Reduced abundance and altered composition of microflora populations 

have been observed in the vicinity of point source emissions of lead and in 

an area contaminated with metal mine waste. Corresponding to these changes, 

the accumulation of litter and alterations in soil parameters have been 

reported. Lead was the predominant heavy metal contaminant in these areas 

(Jackson and Watson, 1977; Bisessar, 1982; Williams et al., 1977c). 

Although these field observations suggest the inhibitory effect of 

lead on microbial activity in certain heavily contaminated areas, their 

usefulness in assessing the environmental impact of lead is limited 

for the following reasons: 

1) the inability to isolate the effect of lead from the confounding 

effects associated with other components of point source emissions 

and other heavy metals; and 

2) the lack of quantitative information concerning the effect of other 

environmental factors that influence the decomposition rate, i.e., 

temperature and moisture conditions (Smith, 1981). 

3. Fauna 

a. Exposure 

The principal pathway of exposure for fauna is through dietary intake 

(CD, p. 8-26). Fauna of the grazing food-chain are affected most directly 

by deposition of lead on vegetation. Others, such as predators, are 

affected more indirectly by lead moving through the food-chain, thus 
P.23 

VIII-10 

raising concerns about the potential accumulation and biomagnification 

of lead at higher trophic levels. While biomagnification (biological 

concentration of lead from one trophic level to the next) has not been 

observed in vertebrate food-chains (NAS, 1980; Williamson and Evans, 

1972), available data suggest that the biomagnification of lead does 

occur in invertebrate food-chains (NAS, 1980; Getz et al., 1977; 

Wade et al., 1980; Watson et al., 1976). Thus, non-toxic levels of lead 

taken up and accumulated by invertebrates may produce toxic effects in 

their predators. Although support for this potential route of exposure 

is provided (Bull et al., 1983a; Getz et al., 1977; Gish and Christensen, 

1973), the occurrence of lead burdens in prey high enough to cause toxic 

effects in predators is variable (Wade et al., 1980). 

b. Field and Laboratory Evidence of Lead-Induced Effects 

The available data on lead-induced effects in invertebrates are very 

limited and are not sufficient to establish quantitative relationships. 

Decreased soil invertebrate.abundance, suggesting potentially significant 

alterations in soil decomposition processes, has been observed, however, 

in the vicinity of point source emissions of lead and in the area of a 

metal mine waste site (Watson et al., 1976; Williams et al., 1977c; 

Bisessar, 1982). Due to the presence of other pollutants and heavy metals 

in these areas, it is not possible to attribute the observed reductions 

to lead alone. 

Very few field studies reporting lead exposures, body burdens and 

associated effects in wildlife are available. Unusually high lead exposures 

resulting in toxic effects have occurred primarily in waterfowl and livestock. 

Sources of these exposures have typically included lead wastes, paint and 

spent lead shot (unrelated to airborne lead emissions), and contaminated 
P.24 

VIII-11 

forage near lead smelters (NAS, 1980; Forbes and Sanderson, 1978). With 

the exception of cattle and waterfowl, incidence rates of lead poisoning 

in terrestrial fauna are generally unavailable (Forbes and Sanderson, 

1978; Botts, 1977) and difficult to verify. 

Although lead burdens in mammals are elevated relative to natural 

background levels (CD, p. 8-29, 8-30), with burdens positively correlated 

with proximity to roadways (Williamson and Evans, 1972; Quarles et al., 

1974), it is uncertain if exposures are resulting in animal burdens high 

enough to be of concern. This uncertainty results from a limited data base 

of field observations that report conflicting findings. Body burdens of 

lead that have been identified to cause effects in animals have not been 

observed in certain high lead environments, i.e., roadsides and smelter 

areas (Forbes and Sanderson, 1978; Getz et al., 1977). Other studies, 

however, indicate that elevated lead burdens associated with effects may 

occur in livestock grazing near smelters and in small mammals in areas 

adjacent to highways, mining sites and smelters (NAS, 1980; Clark, 1979; 

Quarles et al., 1974). 

When assessing the effects of lead on domestic animals and wildlife, 

it is important to consider the more subtle effects that are not readily 

discernible in field observational studies. Drawing on animal toxicological 

studies discussed in the CD and referred to in Appendix D, it is clear 

that lead can affect a wide range of critical functions such as heme 

synthesis, neurobehavioral function, and reproduction and development. 

Investigation of these effects has been limited, however, primarily to 

laboratory animals. In part because of species differences in susceptibility (Forbes and Sanderson, 1978) and a lack of sufficient quantitative 

exposure/uptake/response data in natural habitats, results from controlled 
P.25 

VIII-12 

animal studies have not been extrapolated to animals in natural environments. 

While current analyses and understanding of the potential effects of 

lead in domestic animals and wildlife species are considerably less definitive 

than for humans, the available data strongly suggest that animals may be at 

risk. When assessing much of the same data in 1980, the Committee on 

Lead in the Human Environment of the National Academy of Sciences concluded 

that animal sensitivity to lead might equal or exceed that of man (NAS, 

1980). 

II. Aquatic Ecosystems 

A. Behavior of Lead in Water and in Sediments 

The capacity of surface waters to retain lead in solution at equilibrium 

is dependent upon the physical and chemical water quality parameters of the 

particular aquatic environment (NAS, 1980). In addition to physical and 

chemical parameters that determine lead's solubility, biological conditions 

can influence the behavior of lead in aquatic systems (Rickard and Nriagu, 

1978), and, hence, its availability and potential impact in aquatic 

biota. Although lead is readily complexed in natural water systems (CD, 

p. 6-33), concentrations exceeding 100 pg Pb/1 (lead in solution) have 

been reported for surface waters receiving urban runoff and sewage and 

industrial effluents (NAS, 1980). 

Due to the lack of major exports of lead from freshwater ecosystems, 

these systems function as potential sinks for lead loading (McNurney et 

al., 1977; Getz et al., 1977), with the sediment as the primary sink for 

lead similar to soil in terrestrial ecosystems (Rickard and Nriagu, 

1978). The sedimentation of lead depends on a number of environmental 

factors (CD, p. 8-13), and the retention of this heavy metal within the 

sediment is influenced by the substrate type (McNurney et al., 1977; 
VIII-13 

Wershaw, 1976; Newman and Mcintosh, 1982). Over the past century, a 

trend of increasing deposition of lead in the sediments of freshwater 

systems has been observed (CD, p. 5-1, Figure 5-1), with elevated lead 

concentrations observed in sediments draining urban areas relative to 

rural areas (McNurney et al., 1977; Getz et al., 1977). 

As a result of the accumulation of lead in the sediments of freshwater systems, the soluble fraction comprises only a small percentage of 

the total lead burden (Rickard and Nriagu, 1978; Wershaw, 1976). Because 

of potential regeneration, however, the reservoir of lead in the sediment 

can become a source of soluble lead even after the discontinuation of 

lead inputs (Wershaw, 1976). The significance of this mechanism to 

increase the availability of waterborne lead to aquatic biota may be most 

pronounced in water bodies in which complexed lead in the sediment remains 

at the water-sediment interface. Field observations indicate that this 

situation does occur (Getz et al., 1977). 

B. Effects in Aquatic Biota 

This discussion of the effects of lead in aquatic biota focuses on 

vertebrates (fish) because this component of aquatic ecosystems appears 

most sensitive to this heavy metal and, relative to other taxonomic groups, 

a more extensive data base is available. There is some evidence, however, 

of effects of lead in other aquatic biota at low concentrations of waterborne 

lead. Although the data are limited, lead-induced effects (e.g., increased 

mortality, impaired reproduction) in certain aquatic invertebrates have 

been reported at concentrations as low as 19 - 30 pg Pb/1 (CD, p. 8-33, 

8-34; Borgmann et al., 1978; Biesinger and Christensen, 1972). 

Hematological and neurological changes have been observed in fish 

exposed under laboratory conditions to waterborne lead concentrations between 
P.27 

VI11-14 

8-120 pg Pb/1 (Table 8-3). While the hematological system of fish may 

be capable of compensating for lead-induced changes, the neurological 

effects, black tails (an early indicator of spinal deformity) and spinal 

curvature (which increases mortality and prevents successful reproduction) 

are of clear concern (Hodson et al., 1978a). These findings are conservative 

because sensitivity to lead is species-specific and trout exhibit increased 

susceptibility to lead relative to other fish (Wong et al., 1978), and 

the effects observed at the lower limits of the concentration range may 

have been enhanced by the relatively soft water conditions used in the 

experiments (Davies et al., 1976). 

Extrapolating these results to natural systems is constrained by the 

many factors that influence the toxicity and bioavailability of lead, 

i.e., form of lead, route and length of exposure, pH, hardness and temperature 

of water, and life stage of-organism (Hodson, 1979; Hodson et al., 1978b, 

1979; Wong et al., 1978). Decreased pH level appears to increase the 

uptake of waterborne lead by fish although the precise mechanism of 

action is unclear (Hodson et al., 1978b). These data suggest that lead 

will have its greatest effect on fish in soft water, low pH aquatic 

systems because these systems have a greater capacity to retain lead in 

solution at equilibrium before reaching chemical saturation (Hem, 1976), 

and the adverse effects of lead in fish are closely related to dissolved 

lead content (Hodson et al., 1978b; Wong et al., 1978). 

Ill . Staff Conclusions and Recommendations 

The available laboratory and field data indicate that at concentrations at or below those found in certain high lead environments, lead 

can: 1) affect certain plants (e.g., inhibition of photosynthesis, reduced 

growth, changes in composition), microbes (e.g., reduced abundance), and 
Table 8-3. EFFECTS OF WATERBORNE LEAD IN AQUATIC VERTEBRATES (FISH) 

Effect Fish Exposure Conditions 

Water 

Parameters Reference 

Neurological changes, 

enzyme activit y 

inhibition , behavioral 

changes3 

Trout, sunfish, 

goldfish 

Variable exposure t o Variable0 

10-100 ug Pb/1 

Wong et al, 

(1978) 

Neurological changes 

(Black tails, spinal 

curvature) 

Rainbow 

trout (eggs) 

Chronic exposure to 

8 pg Pb/1 

Hardness 28 mg/l 

as CaC03 

(soft water) 

pH 6.7-7.3 

Davies et al. 

(1976) 

Neurological change 

(Black tails) 

Rainbow trout 

(eggs and young 

fish) 

30 week exposure to 

22 pg Pb/1 

Hardness 135 mg/l 

as CaC.03, pH 8.2 

Hodson et al. 

(1979) 

Neurological change 

(Black tails, spinal 

curvature) 

Rainbow trout 

(young fish) 

30 week exposure to 

120 pg Pb/1 

NR Sippel et al, 

(1983) 

Hematological changes 

(increased number 

red blood cells (rbc), 

decreased rbc volume, 

decreased rbc ALA-D 

activity) 

Neurological change 

(Black tails) 

Rainbow trout 

(young fish) 

Up to 32 week exposure 

to 13 pg Pb/1 

32 week exposure to 

120 py Pb/1 

Hardness 135 mg/l 

as CaC.03, pH 7.7 

Hodson et al. 

(1978a) 

1 

1 — » 

cn 

Hematological changes 

Decreased glutamic 

transaminase activity 

(GOT) 

Decreased hemoglobin 

Oecreased GOT activity 

Brook trout 

(young fish) 

2 week exposure to 

34 pg Pb/1 

2 week exposure to 

58 pg Pb/1 

8 week exposure to 

58 pg Pb/1 

NR 

^Compilation of several sources. 

"Limited information indicates soft water conditions (< 50 mg/l hardness as CaC03 ). 

NR -Not reported. 

Christensen et al, 

(1977) 

ro 

00 
P.29 

VIII-16 

fish (e.g., neurological changes); and 2) alter the composition of 

microbial communities and inhibit invertebrate activity resulting in 

delayed decomposition, reduced nutrient supply, and altered soil properties 

(e.g., lower organic content). With respect to domestic animals and 

wildlife, a qualitative assessment of the available field studies and 

animal toxicological data suggests that animals may be as susceptible 

to the effects of lead as humans. 

The available data also raise concern about the continuing accumulation 

of lead in the soil reservoir that functions as a finite sink of undefined 

capacity. Due to the persistence of lead in the environment, such accumulations are expected to continue as long as inputs exceed outputs. Thus, 

even at relatively low deposition rates lead could affect the ecosystem 

over the long-term. 

The available data are limited, however, and do-not permit any 

definitive findings with respect to concentration-response functions 

associated with the observed effects or provide clear quantitative relationships 

between concentrations of lead in the natural habitat and biologically 

available lead. Data are not available to determine quantitative relationships 

between ambient concentrations of lead and effects in the biota of terrestrial 

and aquatic ecosystems. These limited data do suggest, however, that 

effects of lead on these ecosystems can be significant, although poorly 

defined, particularly with respect to their long-term implications. 

The effects of lead on ecosystems are probably more closely related 

to the deposition and long-term accumulation of lead than to current 

ambient air quality levels. This suggests that a secondary standard for 

lead in the form of a deposition rate may be more appropriate than one 

expressed as an airborne concentration level. Such a deposition standard 
P.30 

VIII-17 

is conceptually appealing because it could be a more effective method to 

provide protection against the welfare impacts of lead. Its application 

at this time is constrained, however, by practical considerations such as 

the absence of sufficient data to develop appropriate deposition targets 

and the lack of reliable methods for measuring both wet and dry deposition. 

Although quantitative relationships are not well enough developed to 

specify the most appropriate secondary standard, the key question is whether 

the range of alternative air quality levels discussed in Section VII would 

provide adequate welfare protection. While this question cannot be answered 

definitively, all but one of the air quality levels discussed in Section 

VII would likely reduce current ambient lead loading. These reductions, 

coupled with reductions achieved by the continued phase-down of lead in 

gasoline (gasoline consumption accounts for 85-90% of total airborne lead 

emissions), would likely mitigate the potential risks of lead-induced 

ecosystem effects occurring in most areas of the country. In urban centers, 

along roadsides, and in the immediate vicinity of major point sources that 

have experienced a long-term, historical accumulation of lead, and where 

the natural soil sinks for lead may be approaching or have exceeded their 

capacity to bind lead, the more sensitive components of the ecosystem 

(e.g., soil microbes) may remain at some risk that is difficult to quantify 

at present. The level of the primary standard chosen from air quality 

ranges discussed in Section VII could, however, provide adequate protection 

from ambient-related exposures for most, if not all mammals both domestic 

and wild. Therefore, given the available data along with their major 

uncertainties, the staff recommends that consideration be given to making 

the secondary standard equivalent to the primary standard in all respects. 
P.31 

APPENDIX A. LEAD METABOLISM AND PHYSIOLOGICAL MEASUREMENT 

1. Lead Absorption 

Environmental lead compounds can be absorbed into the bloodstream from 

the lung after inhalation, from the gastrointestinal tract after ingestion, 

or to a limited extent from direct dermal contact. In addition, fetuses 

absorb lead through the placenta. Some lead that is inhaled or ingested 

passes out of the body before being absorbed, and some lead that is absorbed 

from the lungs or the gut is removed from the blood and excreted. 

The absorption kinetics for each pathway are dependent upon a number of 

factors, including the physical and chemical nature of the lead compounds 

at the time of exposure and the presence of other modifying agents (e.g., 

dietary constituents, other pollutants). Once inorganic lead is abosrbed 

into the bloodstream it is readily transported to other locations in the 

body and does not normally retain any characteristics associated with its 

exposure or absorption route. Dermal absorption is potentially significant 

only for high organic lead exposure in occupational settings or other 

special circumstances. This route, therefore, will not be addressed 

further. 

a) Respiratory Absorption 

Although lead aerosols in ambient air can encompass a broad size range 

depending on proximity to sources and meteorological conditions, most urban 

and rural airborne lead mass is associated with submicron particles, with a 

distinct peak of large particles in the upper end of many of the size distributions (Davidson and Osborn, 1984). Particle size distributions of 

airborne lead mass, collected from various urban, rural and point source 

areas were combined with recent lung deposition data (Chan and Lippmann, 

1980) to estimate the mass fraction deposited in each compartment of a 
P.32 

A-2 

mouth-breathing adult's respiratory tract (Davidson and Osborn, 1984). 

Based on these calculations, it is estimated that on average, about 26 to 

42% of airborne lead particles in these different locations are capable 

of deposition into the respiratory tract of adults. This is generally 

consistent with deposition data on lead particles generated in laboratory 

chambers (Kehoe, 1961; Gross, 1981; Nozaki, 1966; Chamberlain et al., 

1978) and near a highway (Chamberlain et al., 1978) in resting adults 

breathing through mouthpieces. It is estimated that 10-26% of these 

submicron particles deposit in the alveolar region (Davidson and Osburn, 

1984) where absorption into the bloodstream appears to be rapid and 

nearly complete, regardless of the inhaled lead particles' chemical form 

(Chamberlain et al., 1978; Rabinowitz et al., 1977; Morrow et al., 1980; 

Barry, 1975). The remaining 16% of the lead particles, mainly in the 

coarse mode (>2.5 pm) is estimated to deposit in the extrathoracic and 

tracheobronchial compartments of the respiratory tract. Clearance of 

most of this material to the esophagous may be rapid, except for non-hygroscopic 

particles lodged in the tracheobronchial region. From the esophagous, 

the lead particles are either expectorated or swallowed. Lead absorption 

into the blood through the gut is about 40% by mass of coarse-mode inhaled 

particles (MMED ~ 2.9 pm) (Kehoe, 1961). 

Total respiratory absorption of inhaled lead particles for adults 

can be calculated by adding the products of deposition and absorption 

rates for each region of the respiratory tract. Thus, (10 to 26% x 100%) 

for the alveolar region is added to (16% x 40%) for the combination of 

extrathoracic and tracheobronchial regions, yielding an estimate of 

16-32% for total respiratory absorption of inhaled lead particles among 

adults in various U.S. atmospheres. 
P.33 

A-3 

Given that particles larger than 1 to 3 pm which predominate near 

lead smelters (within 2-5 km) and other stationary sources (Jennett et 

al., 1977; Davidson and Osburn, 1984) are likely to deposit in the respiratory 

tract with increasing efficiency as particle size increases (Chan and 

Lippmann, 1980), the above estimates may underestimate respiratory deposition 

and absorption of lead particles in these areas. For example, it is 

estimated that 15-55% of 5 ym particles by mass deposit in the alveolar 

region and 8-45% deposit in the tracheobronchial region of mouth-breathing 

adults (Chan and Lippman, 1980). The upper bounds of these ranges are 

2 - 3 times higher than those estimated for airborne lead particles in 

various urban, rural, and point source atmospheres, previously discussed. 

In the absence of extensive lead particle size data around lead point 

sources that would allow a separate analysis to calculate respiratory 

deposition and absorption for these areas specifically, it is assumed 

that for adults, total respiratory absorption of inhaled lead particles 

is approximately twice as efficient (i.e., 30-60%) around point sources 

compared to the general case representing typical urban and rural areas. 

Because atmospheric particle size distributions and individual deposition 

characteristics (e.g., mouth versus oronasal breathers) as well as other 

factors (e.g., ventilation rates) vary widely, the above discussion may 

not address potentially important exposure/deposition cases. This is 

especially true for children, whose respiratory deposition and absorption 

characteristics have not been studied experimentally. Age-dependent differences 

in respiratory geometry, air flow conditions, metabolism, and body compartment 

weight must be applied to make projections from adult data. 

The criteria document cites a model that accounts for some of these 

differences in estimating that submicron particles deposit in the respiratory 
P.34 

A-4 

tract of a 10-year child 1.6 - 2.7 times more efficiently than in an adult 

(James, 1978). Although the author states the model should yield a 

"reasonable approximation" for younger children whose lungs are not fully 

developed, Hoffman et al. (1979) calculated significantly higher alveolar 

retention rates for submicron nuclide aerosols in 2-8 year old children 

compared with 10 year olds. Another limitation of the James model is its 

assumption of uniform deposition throughout the entire lung surface, 

ignoring enhanced deposition in airway bifurcations and other "hot spots" 

in large bronchi (Schlesinger and Lippmann, 1978; Martonen, 1983). This 

may be an important factor even for submicron lead aerosols whose toxicity 

is largely systemic, since clearance from such hot spots will be diminished 

and because absorption of soluble lead compounds can occur in the upper 

bronchial airways. Consequently, it is uncertain whether the deposition 

and absorption factor range of 1.6-2.7 derived from James (1978) is 

applicable to children, especially those in the age range of our sensitive 

population. 

Assuming that this model is applicable to younger children, the 

absorption factor becomes: (0.16 to 0.32) x (1.6 to 2.7) = (0.26 to 0.86) 

for mouth-breathing children in general urban/rural atmospheres and 

similarly, 0.48 to 1.6 for mouth-breathing children living near point 

sources. (Obviously, a respiratory deposition/absorption efficiency factor 

greater than 1.0 is impossible.) Since most people shift to mouth breathing 

only temporarily during exercise or other activities (e.g., conversation) 

or during illness (e.g. congestion), these estimates, based on mouth-breathing 

individuals, likely overestimate total respiratory deposition and absorption 

over the course of a day. Therefore, daily respiratory absorption rates 
P.35 

A-5 

of 25 to 50% and 50% to 75% are assumed for children living in general urban/ 

rural areas and near point sources, respectively. 

b) Gastrointestinal Absorption 

The absorption in the gastrointestinal (GI) tract of lead-containing 

compounds present in food, water, soil, dust, paint chips, or other materials 

that a child may ingest is dependent upon the physical/chemical form of the 

material, the composition of the diet, and the age and physiological status 

of the individual. 

Young children have a higher intake of lead on a body weight basis 

because of higher requirements for calories, fluid, and air (Mahaffey and 

Michaelson, 1980). In addition to ingesting more lead, children up to 8 

years of age absorb between 42 and 53% of ingested dietary lead compared 

with 7 to 15% in adults (Alexander et al., 1973; Ziegler et al., 1978; 

Kehoe, 1961; Chamberlain et al., 1978; Rabinowitz et al., 1980). 

These rates do not reflect the wide degree of inter-subject variability 

observed in the studies nor other factors that influence absorption in 

children. For example, absorption rates 2 to 4 times higher were observed 

in adults following fasting periods of 4 to 16 hours (Blake, 1976; Chamberlain 

et al., 1978; Heard and Chamberlain, 1982; Rabinowitz et al., 1980). 

Such increases can be expected among children who skip meals, a particular 

problem among lower income groups (Koh and Caples, 1977). Regular eating 

patterns do not insure minimized dietary lead absorption, however. Based 

on several animal studies, clinical investigations, and epidemiological 

surveys, children with diets deficient in calcium, iron, phosphate, zinc, 

copper, vitamin D, protein, lipids, or lactose can be expected to absorb 

and retain lead to a greater degree (Mahaffey and Michaelson, 1980; Rosen 

et al., 1981; Chilsolm, 1981; Heard and Chamberlain, 1982; CD, Table 10-4). 
P.36 

A-6 

This phenomenon may partially explain the enhanced neurotoxicity of 

lead in animals with nutritional deficits (Mahaffey and Michaelson, 1980). 

The importance of nutritional interactions with lead absorption and possibly 

toxicity is particularly significant for young children because of their 

large fluxes in relative nutrient status. These interactions can only be 

estimated qualitatively with present information, however. Although 

nutritional deficiencies are more pronounced among lower income children 

(Mahaffey and Michaelson, 1980; Owen and Lippmann, 1977; Hambidge, 1977), 

they exist in children of all socio-economic strata (CD, p. 10-41). 

The ingestion of non-food items such as dust, soil and dirt through 

normal hand-to-mouth activities in children constitutes the greatest 

contribution of atmospheric lead to a typical child's total lead exposure 

(CD, Table 7-25). Animal experiments indicate that lead of variable chemical 

form in soil or dust is as available for absorption as food lead (Dacre and 

Ter Haar, 1977) and in vitro studies demonstrate that the acidity of the 

human stomach is adequate to extensively solubilize lead assimilated from 

soil and dust (Day et al., 1979; Harrison, 1979; Duggan and Williams, 1977). 

Based on these data and the fact that ingestion of such materials occurs 

other than at mealtimes, allowing for potentially enhanced absorption due 

to the previously discussed fasting factor, the CD estimates that 30% 

of the lead ingested in dust and soil is absorbed in a child (CD, p. 10-10). 

An inverse relationship was found between particle size and gastrointestinal 

absorption of lead, especially in the range of 1-100 ym, such that a 6 um 

dietary lead particle was absorbed five times as efficiently as a 197 ym 

particle (Barltrop and Meek, 1975). There is little information to assess 

whether the conversion in the physical form of atmospheric lead-containing 

particles once inside the complex geochemical matrix of soil or as dust 
P.37 

A-7 

would affect their bioavailability and, consequently, toxicity. Thus, 

all atmospheric lead particles that have deposited are considered to have 

the same absorption rate (30%) if ingested. 

2. Transplacental Transfer 

Lead uptake via this pathway occurs rapidly beginning in the twelfth 

week bf gestation and increases throughout development (Barltrop, 1969). 

Cord PbB levels are slightly lower than maternal levels and are significantly 

correlated with maternal exposure (Alexander and Delves, 1981; Rabinowitz 

and Needleman, 1982; Ryu et al., 1978). 

3. Physiological Retention, Distribution, and Excretion 

The initial uptake of lead from the lungs or gut is to plasma, where 

it is rapidly distributed to red blood cells, bone, and virtually all of 

the organs and tissues of the body (Chamberlain et al., 1978). The level 

of lead at any one site and time is determined by complex, dynamic interchanges 

among the various tissues and fluids that affect their respective affinities 

for lead. With consistent exposure for an extended period, a near steady-state 

distribution within the body is achieved (CD, p. 10-13). A primary goal of 

more refined lead uptake estimates to be used in conjunction with the biokinetic 

model discussed in Section V.A.2 will be to assess how short-term exposures 

superimposed on a long-term uptake pattern affect this steady-state 

distribution in children. 

a) Retention and Excretion 

In children, 47 to 58% of ingested lead on average is eliminated in 

the feces without prior gastrointestinal absorption (Alexander et al., 

1973; Ziegler et al., 1978), while at least as great a percentage of inhaled 

lead particles fail to deposit in a child's respiratory tract, assuming 

that the previously-discussed James (1978) model is accurate. In adults, 

40-60% of the lead absorbed from the gut or lungs into the blood is 
P.38 

A-8 

excreted in urine with a half-life between 18 and 37 days depending 

on initial blood lead or dosage (Chamberlain et al., 1978; Rabinowitz et 

al., 1976; Griffin et al., 1975). This rapidly excreted fraction is estimated 

to be only 16% of the absorbed lead in infants (CD, Table 10-3, based on 

Ziegler et al., 1978). 

Lead is excreted into the urine by the kidneys, both by glomerular 

filtration and transtubular flow (Goyer, 1968). Lead-induced renal effects 

(Appendix D.4; CD, Section 12-5) may compound toxicity by interfering 

with urinary lead excretion. 

Absorbed lead can also pass from the blood through the intestinal 

wall into the gut and be eliminated with the feces, as is the ingested and 

inhaled lead that is swallowed and not absorbed (Chamberlain et al., 1978). 

The excretion rate of this "endogenous" fecal lead appears to be roughly 

equal in children and in adults (CD, Table 10-3). A small portion of 

absorbed lead is excreted in sweat and milk, or is stored in tissues that are 

later shed (e.g., hair, nails, deciduous teeth) (Rabinowitz et al., 1973). 

The balance of the absorbed lead is transported to soft tissues and 

bones where it may be stored for months to years or reabsorbed into the 

blood. In adults, between 1 and 4% of daily lead intake is retained 

in the body (Chamberlain et al ., 1978; Rabinowitz et al., 1977; CD, Table 

10-3) while children (2 months to 8 years of age) are estimated to retain 

between 18 and 33% (Alexander et al., 1973; Ziegler et al., 1978; CD, 

Table 10-3). 

b) Distribution 

Lead that remains in the body can be divided conceptually into separate 

physiological pools. The largest pool is skeletal (i.e., bones and teeth) 

which accounts for about 94% of total body lead in adults and about 
P.39 

A-9 

73% in children under 16 years of age (Rabinowitz et al., 1974; Barry, 

1975). The remaining body burden of lead resides in soft tissue and 

blood. Under typical conditions, more than 99% of blood lead is bound 

within red blood cells, primarily to hemoglobin (DeSilva, 1981), although 

it is the very small fraction transported in plasma and extracellular 

fluid that carries lead to the various body organs (Baloh, 1974). 

The selective accumulation of lead in the heart (aorta), kidney cortex, 

and liver (Barry, 1975, 1981; Gross et al., 1975) may be associated with 

the sensitivity of these organs to elevated lead exposure. The greater 

capacity of young animals to retain lead in their tissues, particularly 

in the brain, may help to account for the persistence of neurotoxic 

effects of various types in young animals (CD, 12.4.3.1.5) and children 

(CD, 12.4.2.2.2) long after external lead exposure has ceased and PbB levels 

have declined to "normal". Furthermore, relative uptake characteristics 

and distribution patterns of lead among the regions of the brain may be 

factors in lead neuropathology (Grandjean, 1978; Klein and Koch, 1981). 

Within the cell, there is selective uptake of lead into nuclear 

inclusion bodies and mitochondria (Barltrop, et al., 1971; Castellino 

and Aloj, 1969), which is consistent with lead-induced interference of 

normal processes in these organelles such as disrupted energy metabolism 

and ion transport, and possible genotoxicity (CD, 12.2.1 and 12.7). 

4. Kinetics and Physiological Indices of Lead Exposure 

Skeletal lead is relatively inactive physiologically, with an approximate 

biological half-time in normally exposed humans of 17-28 years (Rabinowitz 

et al., 1976). When lead exposure is reduced or terminated, lead is 

released from the skeleton so that the declines in blood lead levels and 
P.40^ 

A-10 

excretion rates are less than would be predicted for the amount absorbed. 

This is especially evident in occupationally exposed adults (O'Flaherty 

et al., 1982). Lead turnover rates in dense cortical bones (e.g., teeth, 

tibia, femur) are substantially slower than in spongy trabecular bones 

(e.g. rib, vertebrae) (Steenhout, 1982). Long-term resorption rates of 

lead stored in the skeleton, though difficult to measure, have been derived 

from isotopic ratio and radiolabel tracer studies (Chamberlain et al., 

1978; Manton, 1977). About 25% of an adult's PbB is estimated to result 

from eventual re-entry of skeletal lead (Chamberlain et al., 1978). 

Chamberlain (1983) proposes that the blood lead/air lead ratios discussed 

in Section V.B. be multiplied by a factor of 1.3 to allow for possible 

re-entry into the blood of lead transferred to bone or other long-term 

storage. 

The release of lead from the skeleton may be accelerated under some 

stressful conditions, such as chelation therapy, nutritional deficiencies, 

hormonal imbalances, bacterial infections, and possibly lactation with 

subsequent transfer of both lead and calcium from mother to fetus or newborn 

(Bethea and Bethea, 1975; Rosen and Wexler, 1977; Keller and Doherty, 1980; 

Gross and Pfitzer, 1974). As a result, children, whose skeletal systems 

are more prone to some of these demineralizing conditions, are at increased 

risk of remobilization of skeletal lead. 

The lead content of deciduous teeth provides an index of historical 

exposure over several years since teeth accumulate lead up to the time of 

shedding or extraction. Tooth lead levels appear to be proportional to 

exposure (Needleman and Shapiro, 1974; Steenhout and Pourtois, 1981) and 

to blood lead levels (Shapiro et al., 1978), and are becoming more commonly 

used as an exposure index in population studies of lead health effects in 

children (e.g., Needleman et al., 1979; Winneke et al., 1982a, 1983; 
P.41 

A-ll 

Ernhart et al., 1981; Smith et al., 1983). Uniform measurement techniques 

are required to insure comparability in future studies since the absorption 

of lead varies depending on the type of tooth (e.g., incisor versus molar) 

and the constituent matrix within the tooth (e.g., primary and secondary 

dentine, enamel). Although tooth lead levels are not useful in appraising 

current exposure, reliable techniques of in situ tooth analysis are being 

developed such as X-ray fluorescence (Shapiro et al., 1978) which, when 

combined with serial blood measurements, could provide indices of ongoing 

uptake of lead in target organs. 

While most of the body burden of lead appears to be toxicologically 

inactive due to its storage in bone and other possibly "protective" pools 

in soft tissue such as nuclear inclusions and atherosclerotic plaque deposits 

(Cramer et al., 1974; Barry, 1975), the fraction of mobile lead in soft 

tissue and blood available to biological sites of action determines the 

degree of potential toxicity to the organism. The most useful index of 

this active fraction and of imminent toxicity may be the amount that is 

excreted in response to administration of a chelating agent, such as EDTA 

or penicillamine (CDC, 1985; Chilsom et al., 1976; Chilsom and Barltrop, 

1979; Saenger et al., 1982; Piomelli et al., 1984). Chelatable lead 

apparently comprises a fairly large labile body pool made up of soft 

tissue lead and a mobile compartment within bone (CD, p. 10-25). 

In contrast to skeletal lead, turnover in soft tissues and blood 

is rapid, with a residence time of four to six weeks in adults (Rabinowitz 

et al., 1976; Griffin et al., 1975), and possibly much shorter in children 

(Duggan, 1983). Despite this transience, lead added to and removed from 

these pools reaches equilibrium with relatively constant exposure. A 

change in lead exposure and absorption shifts the balance to a new 
A-12 

steady state of dynamic equilibrium within about 60 days although changes 

in PbB levels may be noted immediately (Tola et al., 1973; Rabinowitz et al., 

1973; Griffin et al., 1975). The equilibration period in children 

may be quite different given their accelerated skeletal metabolism and 

apparently increased lead resorption rates from bone, as well as the 

shorter half-life of lead in their blood (Duggan, 1983). It does not 

appear that with continuous dosing lead accumulates in the blood, although 

it may do so in other tissues (Kehoe, 1961; Purser et al., 1983). 

In contrast to tooth lead measurements which reflect lead exposures 

integrated over years, a single blood lead measurement is limited to 

reflecting primarily steady state exposures over recent months, although 

a PbB level may respond to short-term changes in exposure in proportion 

to the initial PbB content. Under conditions of intermittent exposures 

and rapid growth, as is the case with children, blood lead provides only 

a static picture of a dynamic process that includes intake, excretion, 

storage, and mobilization. A high degree of variability in PbB levels 

was frequently observed in children sampled semi-annually from birth 

through two years of age (Rabinowitz et al., 1984a), while older children 

(4-12 years) display greater stability (David et al., 1982). In addition, 

blood lead is only an indirect indicator of lead levels at critical sites 

in the various organs and tissues (Azar et al., 1973; Grant et al., 

1980). For instance, levels of mobilizable lead (CaNa2 - EDTA) in 26% of 

"asymptomatic" children with moderate elevations in blood lead (30-49 pg/dl) 

were similar to chelatable lead values obtained in children with overt 

lead toxicity (Piomelli et al., 1984). Again, this limitation of blood 

lead as an index is especially evident with abrupt changes in exposure 

because of lead's shorter retention time in blood compared with other 
P.43 

A-l 3 

parts of the body, particularly in the brain of the developing organism 

(Bjorklund et al., 1981; Momcliovic and Kostial, 1974). 

Despite the limitations, blood lead has been the most widely used 

index of exposure because of the ease and relative safety of its collection 

and measurement. In future research there should be increased use of serial 

blood measurements in combination with tooth lead analysis, or other indices 

that reflect changes in tissue lead burdens with changes in exposure. 
P.44 

APPENDIX B. ESTIMATES OF LEAD UPTAKE 

For each of the numbered lines in Table 5-1 in the integrated lead uptake/ 

biokinetic model, the assumptions and estimates used in calculating average 

lead uptake for children from the various exposure pathways are discussed 

in the correspondingly numbered paragraphs below. 

1. Outdoor air lead: For purposes of this analysis, it is assumed 

that each air lead concentration analyzed is maintained at a constant 

level and therefore represents the maximum average (e.g., either quarterly 

or monthly) allowable under any given concentration. The possible impact 

of daily variations in air concentrations on uptake is assumed to be small 

given the equilibration period for lead in blood (2 months in adults), the 

relatively small contribution direct inhalation of lead has on total exposure, 

and the modulation of lead levels after deposition and integration of lead 

particles in the environment. It is also necessary to address potential 

differences between lead levels monitored by stationary samplers and actual 

exposures of children to airborne lead. Such differences arise from various 

vertical and horizontal dispersion patterns of lead over complex micrometeorological 

conditions (e.g., urban street canyons). For instance, lead levels decrease 

significantly with distance and with height near roadways and point sources 

(Huntzicker et al., 1975; Landrigan et al., 1975; PEDCo, 1977, 1981). 

Short- and long-term roof-top lead levels in New York City were about 

60-80% of street level readings (Lioy et al., 1980; Bauman et al., 1982). 

Despite such spatial gradients and inter-site variability, it is assumed 

that the currently designed lead monitoring network will adequately differentiate 

pollutant variability and instances of significant excursions, and that 

given the relatively small contribution of inhaled outdoor airborne lead 

to total exposure to atmospheric lead, the level monitored by a fixed 

sampler is a reasonable representation of outdoor, inhalable lead exposure. 
P.45 

B-2 

2. Indoor air lead: The penetration of atmospheric lead into residential 

structures depends on the size of the lead particles, meteorological conditions, 

and the permeability of the windows, doors, and walls of the home. A range 

of indoor/outdoor ratios has been found (0.3-0.8) for different cities and 

structures (Yocom et al., 1971; Yocom, 1982; General Electric Company, 

1972; Moscheandras et al., 1981; Halpern, 1978; Berk et al., 1981; Tosteson 

et al., 1982) and is applied to the urban situation. Near point sources 

where large particles predominate and infiltration into homes is low, the 

ratio appears to be closer to 0.3 (Cohen and Cohen, 1980). 

3. Time spent outdoors: The amount of time spent between indoor and 

outdoor environments varies among young children depending on their stage 

of development (i.e., infant, toddler, pre-school), season, geographical 

location, and family behavior. For present purposes a range of 2-4 hours 

per day spent outdoors (and therefore 20-22 hours spent indoors) is considered 

a reasonable average (CD, p. 7-42). 

4. Time weighted air lead concentrations for each level is estimated 

by: [(outdoor concentration x time spent outdoors) + (indoor concentration 

x time spent indoors)] •*• 24 hours. 

5. The volume of air breathed each day is dependent on age, body 

size, lung capacity, altitude, and activity of the child. For instance, 

ventilatory volume can increase three-fold during strenuous exercise 

(Cotes, 1979). There are few data for young children and the estimates 

of 4.6 m3/day (ICRP, 1975), 6 m3/day (Nutrition Foundation, 1982), and 10 

m

3/day (CD, p. 7-39) for 2-year olds have been used to construct a range of 

average ventilation rates. 

6. The range of total lead intake by inhalation for each air lead level 

is computed by multiplying both the estimated upper and lower bound 
B-3 

time-weighted average concentrations of air lead by upper and lower bound 

estimates of the volume of air respired per day. 

7. Respiratory deposition and absorption: Only a portion of inhaled 

lead is deposited in the lungs and subsequently absorbed into the bloodstream. 

The deposition efficiency of lead particles depends primarily on their size 

and the physiology and rate of breathing of the individual. In Appendix A 

(Section la), a respiratory deposition/absorption rate of 25 to 50% is 

calculated for young children living in typical urban/rural areas, while 

a rate of 50 to 75% is calculated for those living near point sources. 

8. Total lead uptake from the air is the product of total intake 

and the lung deposition/absorption factor. 

9. Average dietary lead consumption: In deriving these estimates, it 

is necessary to make several generalized assumptions that do not account 

for spatial and temporal variations in the addition of atmospheric lead to 

the diet. For example, with the exception of self-sufficient households, 

most food is raised, packaged, and consumed in different locations, thereby 

blending the effects of different atmospheric lead levels from around the 

country. Furthermore, there may be a time lag between lead's introduction 

into the atmosphere and its incorporation into, and ingestion via the diet. 

Nevertheless, it is clear from the most recent data that deposition on and 

absorption into crops by lead throughout the country serves as a significant 

route of animal and human exposure to atmospheric lead (CD, Table 7-18). 

The recent EPA revisions to the gasoline lead content phasedown schedule 

(EPA, 1985b) whereby the standard is reduced from 1.10 grams per gallon 

of leaded gasoline (gplg) to 0.10 gplg, effective January 1, 1986, can be 

expected to eventually reduce dietary lead consumption in relation to reduced 
B-4 

atmospheric lead deposition nationwide. 

Given the wide spatial distribution of atmospheric lead over time to 

different populations via the food pathway, it is difficult to reliably 

estimate dietary contributions of lead under alternative air lead levels in 

the future. Estimates of current mean dietary lead intake levels are, 

however, provided in the criteria document (CD, Table 7-25). By applying 

FDA data on lead content of various foods both before and after processing, 

packaging, and preparation, and on dietary patterns (Beloian and McDowell, 

1981; Jelinek, 1982; National Food Processors Association, 1982, Pennington, 

1983; Wolnik et al., 1983; U.S. FDA, 1984), the CD estimates that, on the 

average, 25.8 pg of dietary lead are ingested daily by a 2-year old child 

and that 10.2 pg of that can be attributed to atmospheric deposition of 

lead on vegetation or soil surfaces. The remaining 15.6 pg/day is attributed 

to lead solder and to undetermined sources. It is likely that further 

research will show that the lead estimated to be from undetermined sources 

is part atmospheric in origin and part from industrial metals (CD, p. 7-42). 

Because the U.S. FDA, in conjunction with the National Food Processors 

Association, is actively pursuing programs to further reduce lead in foods, 

the CD estimates that lead in canned foods should eventually decline by 70% 

(CD, p. 7-48). The mean value of 15.6 pg/day currently attributable to 

lead solder and undetermined sources is therefore adjusted by an intermediate 

factor of 35% to 10.1 pg/day. 

The remaining lead in the diet is apportioned to atmospheric lead 

deposition. Most crops are grown, and most animals are raised, in rural 

areas where atmospheric lead has been primarily attributable to gasoline 

lead. It is necessary therefore to estimate the impact of the recent revisions 

to the lead-in-gasoline phasedown schedule so that dietary lead consumption 
B-5 

under alternative air lead levels can be estimated to represent future trends. 

By 1990, the average maximum quarterly value due only to mobile source 

impacts for population-oriented or neighborhood scale monitoring sites 

is estimated under the revised phasedown program to be approximately 0.01 

to 0.02 pg/m3 (Battye, 1985b). Projected remote or rural monitoring values 

were not analyzed. Based on the projections for neighborhood scale monitors, 

it is clear that regardless of what the lead NAAQS is, the average air lead 

levels in areas away from point sources (where food is generally grown and 

raised) in the U.S. will be below current rural air lead levels. Assuming 

that major point source emissions have predominately local impacts, it is 

estimated that the average air lead level in areas where food is grown and 

raised will be approximately 0.01 pg/m3. In comparison, the CD's estimated mean 

atmospheric contribution to the diet of 10.2 pg/day CD is derived primarily 

from data on foods from crops grown or animals raised in the U.S. since 1979; 

during this period, maximum quarterly average air lead levels in non-urban 

areas have generally been below 0.45 pg/m3 in non-urban areas and below 1.0 

pg/m3 in urban areas (CD, Table 7a-3; EPA, 1984). 

It is, therefore, assumed that for average air lead levels of 0.25, 

0.50, 0.75, and 1.0 pg/m3, the contribution of atmospheric lead to the diet 

will be reduced by roughly a factor of 10 from that estimated under current 

conditions, i.e., 10.2 to 1.0 pg/day. 

For an air lead level that is constantly maintained at 1.25, 1.50 and 

1.75 pg/m3, it is assumed that some non-automotive emissions of lead will 

cause a small effect on dietary lead consumption such that the average 

atmospheric contribution will be reduced approximately five-fold, from 10.2 

to 2.0 pg/day. 
P.49 

B-6 

The total average dietary lead intake for alternative air lead levels 

can then be calculated by adding the atmospheric contribution to the estimated 

lead intake from solder and undetermined sources. 

10. Gut absorption: Only a portion of ingested lead is absorbed into 

the bloodstream. As discussed in Appendix A, the percentage of absorption 

of lead varies greatly depending on the contents of the gut and the nutritional 

status of the child. A range of absorption rates between 42 and 53% 

(Ziegler et al., 1978; Alexander et al., 1973) is assumed for children. 

11. Daily dietary lead uptake is obtained by multiplying rows 10 and 9. 

12. and 13. Dust/soil concentrations: As discussed in Section IV, the 

accumulation of lead in street and household dusts and soils appears to be 

directly related to the volume of traffic, and inversely related to distance 

from neighborhood streets and roads, distance from lead painted and brick 

houses and buildings, and distance from lead smelters and other point sources. 

Despite these observations, there is little information on the relationship 

between different air lead levels and dust levels over time. Predicting such 

a relationship would require the inclusion of many complex variables such as 

deposition rates, chemical and physical characteristics of the lead particles 

and soils, topographic and meteorological conditions, frequency of street 

washings and precipitation, background dust concentrations, and information 

on transport of dust and soil into homes and buildings. Given current data, 

there would be an extremely large amount of uncertainty surrounding any one 

of these variables for different locations. In order to predict outdoor and 

indoor dust concentrations under alternative air lead concentrations, reliance 

is placed on available studies that include measurements of both air levels 

and dust and/or surface soil concentrations (see Table B-l). These data 
B-7 

Table B-l . Summary of Environmental Lead Measurements from Various Locations 

Average 

Air Lead 

(pg/m3) 

0.20 

0.40 

0.28 

0.34 

0.40 

0.68 

0.82 

0.95a 

1.6 - 2.0 

0.27 

0.255 

0.278 

0.19 

0.30 

0.45 

0.8 

3.67 

Average 

Outdoor Soil / 

Dust Lead 

(pg'/g) 

43 

336 

518 

4,881 

81 

339 

262 

_ 

1,200 

631 

398 

438 

81 

112 

114 

466 

2,560 

Average Indoor 

Dust Lead 

(pg/g) 

70 

190 

565 

1,803 

211 

300 

479 

500 

11,000 

412 

424 

331 

80 

-

Location/Reference 

Various Sites in U.K. 

(DOE, 1983) 

Derbyshire, U.K. (lead mining 

area) (Barltrop et al. , 1975) 

Omaha (Angle and Mclntire, 1978) 

New Haven (Stark et al. , 1982) 

Hartford (Lepow et al. , 1975) 

Near non-ferrous smelters in : 

Bartlesville 

Anaconda 

Palmerton 

Ajo (Hartwell et al. , 1983) 

Rural area, Brussels, and near lead 

smelter, Belgium (Roels et al. , 

1978, 1980) 

0.41 690 1,239 Near Arnheim lead smelter, Holland 

(Brunkreef et al. , 1981; Diemel 

et al. , 1981) 

0.82 924 713 Near Toronto lead smelters and in 

3.01 2,416 1,550 cit y (Roberts et al. , 1974) 

1.3 427 1,479 Near El Paso lead smelter (Morse 

2.7b 948f 8,623c et al. , 1979) 

1,700 Near Silver Valley lead smelter 

3,900 (Yankel et al. , 1977; Idaho Dept. 

3,400 Health and Welfare, 1977) 

3,300 

2,400 

10,400 

11,700 

Estimated from SAR0AD monitoring data 

^Geometric annual mean of air lead levels measured within 5 km of smelter 

cGeometric mean of dust and soi l lead levels within 6.4 km of smelter 

0.5 

0.5 

0.7 

3.0 

6.6 

14.2 

16.8 

700 

337 

2,200 

1,300 

1,200 

3,000 

7,474 
P.51 

•3-8 

are limited in that samples were collected only once from a small number of 

locations. It is assumed, however, that both the air and dust measurements 

were representative of lead levels in those areas and that the studies 

employed comparable sampling and analytical techniques. 

Because of historical accumulations of relatively large lead particles 

near primary and secondary lead smelters and other point sources, outdoor 

soil and dust lead concentrations, and consequently potential exposures, 

are significantly greater in these areas, regardless of ongoing emission 

controls. Therefore, separate exposure estimates for individuals living 

near point sources under alternative air lead levels are required. Data 

collected near lead smelters where emissions were comparable to current 

situations will be used to develop outdoor soil/dust lead levels for point 

sources meeting different air lead concentrations. 

Three of the studies not used to develop relationships require comment: 

a) Barltrop et al. (1975) surveyed a rural district in England with minimal 

air pollution, but with high natural soil lead levels as well as being 

contaminated by nearly 1900 years of mining activity. Thus, lead 

deposition on soil surfaces had probably been low for some time, in contrast 

to the other studies in which surface contamination was ongoing or had been 

recently reduced; b) Eight of the ten homes sampled by Lepow et al. (1975) 

were built prior to 1940 and apparently had significant sources of leaded 

paint that had been "corrected" for previous to the study. In addition, 

some of the homes were located close to heavily trafficked roadways, where 

street level air concentrations ranged between 2.2 and 7.7 pg/m3, thus 

lending uncertainty to a dust/air relationship from this study based on 

annual average air lead levels measured at centrally located monitors 

distant from the dust sampling sites; c) The smelter studied by 
P.52 

B-9 

Yankel et al. (1977) operated for several years with severely limited 

air pollution control capacity due to a baghouse fire in 1973. The very 

high soil and dust lead concentrations measured near the smelter then would 

not be expected today with normally controlled emissions. In addition, 

the high indoor dust lead levels measured by Brunekreef et al. (1981) and 

Diemel et al. (1981) near the Belgian smelter were probably due, in part, to 

extremely high lead content (up to 40% by weight) in peeling paint in old 

houses (built around 1900; the children in these houses were excluded from 

analysis of blood lead levels). 

With these exceptions, the studies listed in Table B-l appear to 

have sampled a broad spectrum of homes (e.g. both low and middle class, 

old and modern, with and without leaded paint) and neighborhoods that can 

be considered fairly representative of current U.S. conditions in urban and 

point source areas. Although far from conclusive, the available data 

suggest the generalized relationships between air lead and dust lead concentrations 

presented in Table B-2. The ranges represent boundaries that encompass the 

majority of observed and interpolated values and are used to estimate 

street dust/soil lead and indoor dust lead concentrations under alternative 

air lead levels. 

Interpolations were necessary because of the limited amount of data. 

For instance, Angle and Mclntire (1978) and DOE (1982) report outdoor soil/ 

dust lead concentrations in urban areas with an average air lead level 

of approximately 0.4 pg/m3 to be 81 and 336 ppm (pg Pb/g soil or dust), 

respectively. One of the rural control areas studied by Roels et al. (1978) 

had an outdoor soil/ dust lead concentration of 114 ppm corresponding to an 

air lead level of 0.45 pg/m3. The range of 80-350 ppm is thus estimated based 

on these data. For indoor dust, the former two studies report concentrations 
P.53 

B-10 

Table B-2. Generalized Relationships Between Lead Concentrations 

in Air and in Dusts and Soil* 

Ai r Lead 

(pg/m3) 

0.2 

0.3 

0.4 

0.5 

0.6 

0.7 

0.8 

1.0 

1.25 

1.5 

1.75 

Outdoor 

General 

40-150 

60-250 

80-350 

100-450 

200-600 

250-650 

300-950 

500-1150 

600-1250 

700-1400 

775-1450 

Soil/Dust Lead 

(ug/g) 

Near Point 

Source 

80-375 

200-600 

250-700 

350-800 

450-1000 

550-1150 

650-1300 

750-1450 

850-1600 

1000-1750 

1075-1950 

Indoor Dust 

(pg/g) 

General 

70-100 

70-150 

140-200 

220-300 

250-500 

300-625 

450-700 

525-875 

625-1000 

750-1150 

800-1200 

Lead 

Near Point 

Source 

80-400 

200-600 

350-650 

450-700 

550-750 

600-800 

650-900 

800-1150 

1050-1400 

1200-1700 

1350-1900 

^Derived from environmental surveys in Table B-l. The ranges of dust and 

soil concentrations for each air lead level reflect differences in emission 

sources, distance of measurement sites from these sources (within 5 km for 

point sources) and characteristics of the homes (e.g., permeability, paint 

condition, etc.), and other variables assumed to be representative of real 

world conditions. Values that are underlined represent actual data (rounded 

off where necessary) listed in Table B-l, while the remainder are interpolations 

using the most representative and plausible data in Table B-l and an assumption 

that there is a directly proportional relationship between air lead and 

lead in soil and dust (both indoors and outdoors). 
P.54 

B-ll 

of 190 and 211 ppm; these were chosen as an upper bound estimate for 

0.4 pg/m3 while the lower bound of 140 ppm was derived by multiplying by 

two the lower bound estimate for an urban/rural area with an air lead level 

of 0.2 pg/m3 (70 ppm from DOE, 1982). Outdoor soil/dust lead concentrations 

near point sources that can reasonably be associated with 0.4 pg/m3 were 

derived from Brunekreef/Diemel et al., 1981 (690 ppm) and by interpolating 

the levels measured by Hartwell et al. (1983) concurrently with average air 

lead levels of around 0.25 - 0.28 pg/m3. The resulting estimate is 624 to 

630 ppm and, when combined with the Brunekreef value, results in an upper 

bound estimate of 700 ppm. The lower bound estimate of 250 ppm is assumed 

based on the levels of 80 ppm observed by Hartwell et al. at 0.2 pg/m3, 466 

ppm seen at 0.8 pg/m3 by Roels et al., and 337 ppm seen at 0.5 pg/m3 by 

Yankel et al. This brief example at 0.4 pg/m3 only superficially illustrates 

the limitations of the available data and the judgments necessary to fill 

in gaps using various assumptions, such as the assumption of a direct and 

roughly linear relationship between air lead and surface deposition. It 

must be emphasized that there is a great deal of uncertainty in these 

estimates. For instance, assuming that a decrease in air lead from 1.0 to 

0.8 pg/m3 would result in reduced soil and dust lead concentrations may 

overestimate the impact that such a decrease in lead emissions would have 

on children's exposure, particularly via outdoor soil which tends to retain 

lead for long periods of time. Dust lead levels would likely respond 

relatively more contemporaneously to reduced air emissions, but the necessary 

length of time is difficult to estimate. 

14. Time weighted concentrations of lead in dust and soil that a 

child is exposed to is computed by: [(outdoor soil/dust lead concentration 
P.55 

B-12 

x time spent outdoors) + (indoor dust lead concentration x time spent 

indoors)] * 24 hours. 

15. Amount of dirt ingested: Hand to mouth activity (e.g., thumb 

sucking and finger licking) and immature dietary habits (i.e., the retrieval 

and subsequent consumption of food from dusty surfaces or soil), which are 

normal behavorial characteristics of children up to five years of age 

(Lin-Fu, 1972), make soil and dust major sources of ingested lead for 

children (Charney et al., 1983). There is little information on the amount 

of dirt a child eats in the normal course of a day. Based on a small 

number of direct measurements, Day et al. (1975) estimated that under 

average urban conditions (and after 30 minutes of normal playground activity), 

5 to 50 mg of dirt from a child's hands can be transferred to a typical 

"sticky sweet". A small child playing in dirt easily ingests 10 mg of 

soil/dust with each episode of hand to mouth activity (Drill et al., 1979). 

Ten hand-mouth activities per day (or ingestion of 2 to 20 "sweets"; Day et 

al., 1975) would thus result in the ingestion of 1U0 mg (0.1 g) of dust and 

soil per day (Lepow et al., 1975). This estimate has been used in several 

documents (Drill et al., 1979; NAS, 1980; CD, Table 7-23) and will be used 

here as well. Children with pica who display patterns of repetitive hand-to-mouth 

activity or delibertely ingest paint, plaster, paper and other non-food 

items including dirt may be exposed to considerable amounts of lead compared 

to children who only inadvertantly ingest foreign subsances. Future reductions 

in airborne lead emissions are not likely to significantly alter their 

exposure to lead over the next few years. Regulatory alternatives to protect 

these children are discussed in Section VII. 

16. Lead intake from dust and soil is computed by multiplying the 

time weighted concentration of indoor and outdoor soil/dust concentrations 

by 100 mg. 
P.56 

B-13 

17. Gut absorption of dirt: As discussed in Appendix A, an absorption 

rate of 30% is assumed for ingested lead in dust and soil. 

18. Total lead uptake from dust and soil is obtained by multiplying 

rows 16 and 17. 

19. Total lead uptake is the sum of rows 8, 11, and 18. 
P.57 

APPENDIX C. UPTAKE AND BLOOD LEAD CONCENTRATION 

Several studies are available that provide the necessary linkages to relate 

the exposure/uptake estimates calculated under different air lead levels in the 

integrated uptake model (See Section V.D.I(a)) to children's PbB levels. The 

results of these studies are summarized in Section V.D.l(b) and are discussed 

below, 

a) Dietary Lead Ingestion Studies in Infants 

Studies that have measured dietary lead intake concurrently with 

PbB levels among infants and toddlers are compared in the criteria document 

(Table 11-49). Although precise estimates of dietary lead consumption 

can not be assumed, these studies (U.K. Central Directorate, 1982; Sherlock 

et al., 1982; Ryu et al., 1983) have several advantages: 1) careful control 

and analysis of dietary intake; 2) minimal lead exposure to sources other 

than the diet as the study population (infants) is relatively immobile; and 

3) the impact of total lead exposure (i.e., from all sources) on blood lead 

can be estimated by applying intake/blood lead relationships because tracer 

studies (Chamberlain et al., 1978; Rabinowitz et al., 1976) show no differences 

in the distribution of lead to tissues whether taken up from lung or gut. 

Both the U.K. Central Directorate and the Sherlock et al. studies 

involved infants with relatively high PbB levels and high intakes. Because 

the PbB levels (< 20 yg/dl) and lead intakes of the Ryu infants are more 

relevant, the criteria document concludes that the slope from this study is 

the best available estimate (CD, p. 11-126). The relationship between lead 

intake and infants' blood lead, derived by EPA's analysis of Ryu et al. 

(1983) is: PbB = A + 0.16 PbD, where "PbD" represents dietary lead intake 

and "A" represents non-dietary lead. Applying the gastrointestinal absorption 

rates (42-53%) used in Section V.D.I to convert dietary intake levels 
P.58 

C-2 

into uptake and assuming a background PbB of 4 pg/dl, based on a study of 

blood lead and lead intake in Boston infants (Rabinowitz et al., 1984b), 

yields two possible lead uptake/PbB relationships depending on the absorption 

rate. These relationships are illustrated in Figure 5-1 in the summary of 

uptake/PbB relationships. 

b) Application of Chamberlain and Heard Analysis 

An attempt to relate blood lead and absorbed lead was made by Chamberlain 

and Heard (1981) using epidemiological and clinical data on adult men 

(Williams et al., 1969; Kehoe, 1961; Nordman, 1975; Zurlo and Griffini, 

1973; Fugas and Saric, 1979). Total dietary and airborne lead uptake was 

estimated using calculations similar to those presented in the integrated 

lead uptake model in Section V.A. The resulting eye-fitted curve is shown in 

Figure C-1. The dashed curve is that previously derived in a NAS (1972) report, 

The straight line is the increase in blood lead to be expected from an 

increase in lead uptake based on the assumptions given in Chamberlain et 

al., (1978): a) a fraction, 0.55, of the uptake becomes attached to red blood 

cells; b) the biological half-life of lead in blood is 18 days; c) a factor, 

1.3, is to be allowed for long-term resorption and re-entry into blood of 

some of the lead which is stored in bone; and d) the mass of blood is 5400 

grams With these assumptions: 

A PbB = 0.55 x 18 x 1.3 = 0.34 pg/dl per pg/day 

A Uptake 54 x 0.693 

In order to apply this equation to children, several adjustments are 

required. For example, the mass of blood in young children is estimated 

to fall between 800 and 1500 grams (Wintrobe, 1979). It has been suggesteed 

that the half-life of lead in children's blood is shorter than in adults 

(Duggan, 1983) although no direct measurements have been taken to allow a 

reliable estimate. 
P.59 

C-3 

300 

Uptake. T (pg/d l 

Figure G-1, Relationship between daily lead uptake and blood lead in 

adult men. From Chamberlain and Heard (1931). 
P.60 

C-4 

Because there is no information available on appropriate factors to 

adjust this specific equation to children, the derived relationship from 

adult data illustrated in Figure C-1 is illustrated in Figure 5-1 only 

for comparative purposes, 

c) Lead Balance Studies: Compartmental Models 

To demonstrate a causal relationship between lead in the body and a 

biological change, it would be ideal to know the amount of lead present at 

the site and time of the effect. For instance, if lead is suspected to 

induce neuropsychological changes, a measure of the lead level present in 

nerve cells when the change occurred would be desirable. Living tissues 

can rarely be sampled, and data obtained at necropsy cannot reveal the 

variations in exposure throughout the individual's life. For analytical 

simplicity, these tissues can be grouped together on the basis of lead 

distribution characteristics and body burdens of lead represented as a 

limited number of distinct, homogenous, and well-mixed pools or physiological 

compartments with similar kinetic properties. Mathematical biokinetic 

models have been fitted to data obtained in long-term balance studies and to 

lead isotope tracer experiments that estimate the rates of input to, 

transfer between, and excretion from the different compartments (Rabinowitz 

et al., 1976, 1977; Batschelet et al., 1979; Bernard, 1977; Mallon 1983; 

Harley and Kneip, 1985). Differences in the predictive lead models have 

been discussed by Bernard (1977) and Batschelet et al. (1979). 

Two models are shown schematically in Figure C-2. Compartments as 

defined kinetically are not necessarily congruent with specific tissues or 

organ systems; the three pool model of Rabinowitz et al. (1976) considers 

blood, the most labile soft tissues, and bone marrow (M. Rabinowitz, 

personal communication) as part of the central compartment where exchange 

takes place continuously with the second (soft tissues and labile bone) and 
(a) 

ExcretionsLead in 

Diet, Soil/Oust, 

Other Sources 

(e.g., paint) 

Air Lead 

Lungs 

Bone 

- 20Omg 

7 nq/dav 

~ 7 pg/day 

"sorption 

~48 pg/day 

1 

Blood 

1.9 mg 

~

1 5

 "q/^y Soft tissues 

0.6 mg 

2 pg/day 

"36 pg/day 

Urine 

-12 pg/day 

Bile, hair, 

sweat, etc. 

(b) Absorption 

~35.2 pg/day 

o 

i 

cn 

Hard Bone 

65 mg 

Soft Bone 

2.7 mg 

„6.9 uq/day 

,12.5 ug/day 

h 

9 

V 

1 ' 

Blood 

0.42 mg 

L 57 pg/day 

^ 

* 

w 

Liver 

13 mg 

133 pg/day 

Kidneys 

0.76 mg 

Urine and Feces 

35 ug/day 

Figur e C-2 . Schematic models of lead metabolism in adult men described by (a) kabinowitz et al., 1976 

and (b) Bernard, 1977. The amounts of lead in each compartment, exchanyiny daily between 

compartments, and excreted daily are shown for steady state conditions of continuous 

exposure to inhaled and inyested lead. The amounts of lead shown entering the central 

compartment are the amounts that were assumed to be absorbed daily into the systemic 

circulation from all sources (Hammond et al., 1981). 

b> 
P.62 

C-6 

third (immobile bone lead) pools. The five-compartment model proposed by 

Bernard (1977) consists of pools that are mainly blood, liver, kidney, and 

soft and hard bone. 

The choice of pools or level of aggregation in a model depends on the 

available experimental data, the appropriate time scale, and the predictive uses of the analysis, and is a compromise between accuracy and 

complexity. For example, blood can be broken down into plasma and erythrocytes 

and then further into plasma protein-bound lead, diffusible lead, extracellular 

fluid lead, and erythrocyte proteins. Soft tissues can be broken down into 

brain (hippocampus, medulla, etc.), kidneys, liver, hair, and so on. The 

hard tissue pools can be separated into compact (cortical) and cancellous 

(trabecular) bones, and teeth; within each of these, separate components 

may be needed to model distinct diffusion time scales (Marcus, 1985). 

Because the skeletal system in young children is rapidly developing and is 

both large and kinetically active, it is especially important to model bone 

lead in children. Until such refinements are further tested, a relatively 

simple 3- 5 pool model should provide a framework for predicting lead 

distributions in children. 

These models are helpful in predicting total body burden or equilibrium 

levels of lead over time in any of the presumed kinetic compartments under 

different exposure conditions. The basic assumption of the models is that 

the mass of lead in each of the compartments changes according to a system 

of coupled first-order linear differential equations with constant fractional 

transfer rates. Such models predict that when the lead intake changes from 

one constant level to another, there is a directly proportional change in 

the mass of lead in each compartment and the attainment of a new equilibrium. 
P.63 

C-7 

The rates and magnitudes of these changes are dependent upon the rates of 

lead flux in the tissues and can theoretically be calculated from a compartmental 

model of the appropriate parameters. Support for a first order kinetic model 

for lead metabolism is demonstrated by calculations, using first order models 

of soft tissue and bone concentrations of lead, and other elements (calcium 

strontium, radium), that fit human measurements as well as by using more 

complex ones (Johnson and Myers, 1981; Mallon, 1983). 

PbB levels in adults after exposure for 5 and 19 years have been 

computer simulated by Hammond et al. (1981) based on predictions of the 

Rabinowitz and the Bernard models. The amount of lead absorbed each day 

into the systemic circulation was entered into the computer program as a 

single unit. This daily increment was allowed to be distributed and excreted 

in accordance with the magnitudes of the model rate constants. Table C-1 

gives the predicted PbB levels at the end of the specified exposure periods 

expressed as functions of the total amount of lead absorbed each day from 

all sources. 

It is assumed that these linear mathematical models with distinct rate 

constants for each lead compartment are, in general, valid for relatively 

low to moderate lead exposures (CD, p. ll.A-2). The studies that have 

experimentally determined compartmental models in humans have used a 

very small number of subjects, however, all of whom were adult males, with a 

limited range of exposure conditions. Given the physiological and metabolic 

differences between children and adults, the projected PbB levels calculated 

in Table C-1 have limited applicability and are used for comparative purposes 

only. 

A four-compartment biokinetic model of lead metabolism has been developed 

from data obtained in controlled single dose and chronic lead exposures of 
C-8 

infant (9 months) and juvenile (22 months) baboons (Mallon, 1983; Kneip et 

al., 1983). Dynamic blood measurements and steady state blood and organ 

lead measurements were accurately fitted to predict concentrations of lead 

in blood, liver, and kidney, and bone (the four compartments in which 95% 

of total body lead is contained) (Heard and Chamberlain, 1984). Human 

metabolism and growth patterns were applied in a computer simulation of the 

model that was then successfully validated using human autopsy data. 

The model parameters were revised using measured metabolic data for 

each organ (e.g., bone turnover rates) for children and were used to 

simulate lead organ burdens and concentrations in children with constant 

lead exposures from birth (Harley and Kneip, 1985). Although complete 

model validation is not possible, the revised model is consistent with experimental data on blood lead accumulation following dietary lead uptake among 

infants (Ziegler et al., 1978), and skeletal lead accumulation following 

controlled exposures in adults (Heard and Chamberlain, 1984), and, given 

the available data it appears to provide the best estimates of PbB levels 

in children with continuous lead uptake. 

Table C-2 presents PbB levels predicted by the model for male children 

under different exposures, or lead uptake levels. No differences were found 

between the sexes except at older ames, and predicted PbB levels were 

highest among 2-3 year olds, consistent with results of NHANES II and the 

New York City screening program (Billick et al., 1979). These results are 

applied to estimates of the integrated lead uptake model in Section VII.C.2(a) 

so that children's PbB levels can be estimated under alternative air lead 

levels. 

d) Empirical Relationships Between Blood Lead and Lead in Individual 

Exposure Media 

One of the modeling approaches presented in Section V, and applied in 
P.65 

C-9 

Table C-2. 

Predicted Equilibrated Blood Lead Levels Over Time Among Children with 

Age 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

10 

3.0 

4.0 

3.7 

3.5 

3.6 

3.5 

3.3 

2.5 

2.3 

2.6 

20 

5.9 

8.1 

7.3 

7.0 

7.3 

6.9 

6.5 

5.0 

4.6 

5.2 

Constant Lead Upta 

Lead Uptake 

30 

8.9 

12.1 

11.0 

10.5 

10.9 

10.4 

9.8 

7.4 

6.9 

7.8 

40 

11.9 

16.2 

14.6 

14.0 

14.5 

13.8 

13.0 

9.9 

9.3 

10.4 

kesa 

(yg/day) 

50 

14.8 

20.2 

18.3 

17.5 

18.1 

17.3 

16.3 

12.4 

11.6 

13.0 

60 

17.8 

24.2 

22.0 

21.0 

21.8 

20.7 

19.5 

14.9 

13.9 

15.6 

70 

20.8 

28.3 

25.6 

24.5 

25.4 

24.2 

22.8 

17.4 

16.2 

18.2 

80 

23.8 

32.3 

29.3 

28.0 

29.0 

27.6 

26.0 

19.9 

18.5 

20.8 

aFrom Harley and Kneip (1985). 
P.66 

C-10 

Section VII .C.2, to estimate PbB levels in children exposed to various air 

lead levels is referred to as the "disaggregate" model. In this model, for 

each exposure medium to which children are exposed to airborne lead (i.e., 

air, dust, soil, diet) separate empirical relationships derived from controlled 

experimental, observational of community studies, are applied so that a 

combined exposure function can be estimated under various air lead levels. 

The disaggregate model developed in the CD (Table 13-6) and presented here 

in Table 7-10 relies on the most relevant and reliable of the available 

mathematical relationships. The relationship (»1.97 pg/dl per pg/m^) 

between children's blood lead and inhaled air lead (derived from Angle and 

Mclntire, 1979; Roels et al., 1980; and Yankel et al., 1977) has already 

been discussed in Section V. The studies used to derive the remaining 

relationships in the disaggregate model, between children's blood and lead 

in diet, soil, and dust, are summarized in the following tables. 
Tabl e C-3 . STUDIES RELATING BLOOD LEAD LEVELS (ug/dl) TO DIETARY INTAKES (ug/day) 

Study Analysis Model R» 

Estimated Predicted blood lead 

Blood contribution (ug/dl) for 

Model lead at a given dietary Intake 

D.F. 0 H20 Pb (ug/day) 

Slope froa 100 to 200 

pg/d., ug/dl per pg/d. 

Sherlock et al. 

(1982) study of 

31 adult woaen 

In Ayr 

Sherlock et al. 

(1982) study of 

Infants In Ayr 

coablned with U.K. 

Central Directorate 

Study 

U.K. Central 

Directorate 

(1982) Study 

of Infants tn 

Glasgow 

Ryu et al. (1983) 

study of Infants 

Sherlock et al. 

(1982) 

Sherlock et al. 

(1982) 

U.K. Central 

Directorate 

on Environmental 

Pollution 

(1982) 

EPA 

PBB = -1.4 • 3.6 V PB0 0.52 

PBB = 2.5 • S.O V PBD 

PBB = 17.1 • .056(PBD) 0.19 

PBB = 3.9 * 4.6 V PBD 0.43 

PBB = A • .16P80 

-1.4 

2.5 

17.1 

3.9 

100 

16.7 

23.2 

200 

21.1 

29.2 

300 

24.1 

33.5 

5.6 11.2 16.8 

21.4 26.9 30.8 

16.0 32.0 48.0 

0.034 

0.060 

0.056 

0.053 

0.16 

O 

I 

Source: CD, Table 11-49. 
P.68 

C-12 

Table C-4. ESTIMATES OF THE CONTRIBUTION OF SOIL LEAD TO BLOOD LEAD 

Study 

Range of soil 

lead values 

(pg/g) 

Depth of Estimated Sample 

sample slope (XlO3) size R

2 

Angle and Mclntire 

(1982) study of 

children in 

Omaha, NE 

Stark et al. 

(1982) study 

of children 

New Haven, CT 

Yankel et al. 

(1977) study 

of children 

In Kellogg, ID 

Galke et al. 

(1975) 

study of 

chllren 1n 

Charleston, SC 

Barltrop et 

al. (1975) 

study of 

children 1n 

England 

Neri et al. 

(1978) study 

of children 

1n British 

Columbia 

16-4792 

30 - 7000 

(age 0-1) 

30 - 7600 

(age 2-3) 

50 - 24,600 

7890 

420 - 13,969 

(group means) 

225-1800 

(group means, 

age 1-3) 

225-1800 

(group means, 

age 2-3) 

2" 

V 

3/4" 

2" 

2" 

NA 

NA 

6.8 

1.5 

0.6 

7.6 

4.6 

1075 

194 

82 

87 

103 

.198 

2.2 

2.0 

1.1 

153 

334 

860 

.289 

.300 

.662 

.386 

NANA 

NA 

"NA means Not Available. Source: CD, Table 11-63. 

Table C-5. ESTIMATES OF THE CONTRIBUTION OF HOUSEDUST TO BL000 LEAD IN CHILDREN 

Study 

Angle and Mclntlre 

(1979) study 1n 

Omaha, NE 

Stark et al. (1982) 

study 1n New Haven, 

et 

Yankel et al. (1977) 

study 1n Kellogg, 

ID 

Range of dust 

Lead values (ug/g) 

18-5571 

70-7600 

40-7600 

9-4900 

50-35,600 

Age range 

1n years 

1-18 

6-18 

0-1 

2-3 

4-7 

0-4 

5-9 

Estimated 

slope (XlO3) 

7.18 

3.36 

4.02 

1.82 

0.02 

0.19 

0.20 

Sample 

Size 

1074 

832 

153 

334 

439 

185 

246 

R» 

.198 

.262 

.289 

.300 

.143 

.721 

.623 

Source: CD, Table 11-64. 
P.69 

APPENDIX D. HEALTH EFFECTS OF LEAD 

This appendix discusses and evaluates the information on the various 

human health effects associated with lead exposure. The discussion is 

broken down into the major health effects areas of primary concern and is 

intended to support the assessment in Section VII.C(l) of health risks 

associated with various blood lead (PbB) levels for purposes of determining 

an appropriate lead NAAQS. 

1. Heme Biosynthesis and Related Functions 

Under normal circumstances, heme biosynthesis is a highly efficient 

and coordinated pathway, which produces only sufficient amounts of intermediates and, ultimately, heme to service requirements for hemoglobin --

the blood pigment responsible for transporting oxygen to the tissues -- as 

well as a multitude of functions mediated in most cells by heme-containing 

proteins. These hemoproteins include myoglobin, the hemoglobin of muscle, 

and the mitochondrial respiratory pigments, cytochromes, responsible for 

cellular energetics. Moderately elevated lead exposure has been demonstrated 

to disturb the biosynthetic sequence so as to produce large quantities of 

redundant intermediates that must then be excreted; more severe lead 

intoxication may result in the development of anemia. Lead's interference 

at susceptible stages of the biosynthetic pathway (illustrated in Figure D-1) 

may have important implications for a multitude of organs and systems, 

especially in the growing child, and is briefly reviewed below. 

i. The initial step of the heme synthetic pathway, the formation 

of delta-aminolevulinic acid (ALA) from succinyl-CoA and glycine 

by the mitochondrial enzyme delta-aminolevulinic acid synthetase (ALA-S), 

represents the control point of the pathway. During lead exposure, the 

activity of this rate-limiting enzyme is increased through feedback 
P.70 

D-2 

MITOCHONDRIAL MEMBRANE 

MITOCHONDRION 

HEME 

GLYCINE 

SUCCINYLCoA 

FERRO 

CHELATASE it Pb 

Fe-PROTOPORPHYRIN 

d-ALA SYNTHETASE 

(INCREASE) 

Pb (DIRECTLY OR BY 

DEREPRESSION) t 

Fe 

d-ALA 

d-ALA 

DEHYDRASE 

(DECREASE) 

Pb 

COPROPORPHYRIN 

(INCREASE) 

Pb 

PORPHOBILINOGEN (PBG) 

Figure D-1. Lead effects on heme biosynthesis,from 

CD, Figure 6-1. 
P.71 

D-3 

control apparently in an attempt to compensate for the diminished production 

of heme due to lead's interference (Maxwell and Meyer, 1976). 

ii. In the second step of the pathway, the zinc-requiring enzyme deltaaminolevulinic acid dehydrase (ALA-D), catalyzes the condensation of two 

molecules of ALA to form porphobilinogen. ALA-D is inactivated by lead 

without any apparent threshold, and in erythrocytes, its activity appears to 

be markedly reduced at a PbB around 15 ug/dl in both adults and children 

(Hernberg and Nikkanen, 1970; Wada et al., 1976; Nieberg et al., 1974; 

Secchi et al., 1974; Roels et al., 1975b). Based on several of these 

studies, Zielhuis (1975) calculated that the fraction of children with 40% 

reduction of ALA-D activity increases from about 10 to about 90% as PbB 

rises from 10 to 30 yg/dl. 

The combination of increased ALA-S and decreased ALA-D activity accounts 

for the marked accumulation of ALA in the plasma and body fluids, and 

excess excretion of ALA in urine. The rate of ALA excretion accelerates 

above a PbB of 40 ug/dl in adults and children (Cramer et al., 1974; 

Moore et al., 1980; O'Flaherty et al., 1980). Several studies indicate a 

continuous correlation between urinary ALA (ALA-U) and PbB down to levels 

around 20-25 ug/dl (Meredith et al., 1978; Selander and Cramer, 1970; 

Lauwerys et al., 1974; Chisolm et al., 1976). In light of conflicting 

findings from studies using different measurement techniques, it remains to 

be established whether increases in ALA-U are preceded by elevations in 

circulating levels of ALA in plasma at PbB levels below 40 ug/dl 

(Meredith et al., 1978; O'Flaherty et al., 1980). The criteria document 

concludes that despite a positive bias in absolute ALA values due to measurement contamination by aminoketones not correlated with blood lead, the 

relative changes in blood ALA detected by Meredith et al. (1978) "appear 
P.72 

D-4 

to provide the most plausible basis for the observed correlations with PbB 

levels as low as 18 ug/dl" (CD, p. 12-19). 

While blood indicators of erythropoietic effects of lead may be more 

accessible, they are not the only, nor necessarily the most sensitive 

indicators of heme biosynthesis derangement in other organs (CD, p. 12-26). 

At roughly comparable lead levels associated with such changes in blood 

ALA and ALA-D, inhibitions of ALA-D and elevations in ALA are observed in 

the liver, kidneys, and spleen of adult rats and humans, and to a greater 

degree in the developing brain of young, compared to adult rodents (Millar 

et al., 1970; Secchi et al., 1974; Gerber et al., 1978; Silbergeld et al., 

1982). The impact that elevated ALA may have on the neurological system is 

discussed in Appendix D.l(d). 

It is important to note that because lead is preferentially deposited 

in bone (Appendix A) , the concentrations of lead in the marrow will be 

significantly greater than in the blood during red blood cell formation and 

hemoglobin synthesis in the bone marrow (Albahary, 1972), and the developing 

red blood cells in the marrow will be particularly affected. 

iii. Another effect of lead on heme biosynthesis is its interference 

with the last step of this chain, i.e., insertion of iron into protoporphyrin. 

This is mediated by the enzyme ferrochelatase, which is located in the 

inner matrix of the mitochondria of most cells (Moore et al., 1980). Lead 

impairs the transmitochondrial transport of iron and instead of producing 

heme, the mitochondria accumulate its precursor, protoporphyrin, which 

lacks iron and is incapable of performing its essential respiratory function. 

As a result of lead intoxication in newly forming erythrocytes, protoporphyrin 

(referred to as erythrocyte protoporphyrin or EP) takes the place of heme 

in the specific pocket of the hemoglobin molecule. As the red blood cells 
P.73 

D-5 

remain in the circulation, zinc is rapidly chelated at the center of the 

molecule in the site normally occupied by iron (Piomelli et al., 1982). The 

resulting zinc protoporphyrin (ZPP) is tightly bound in the available heme 

pocket for the life of the erythrocyte, normally 120-130 days (Lamola et al., 

1975). Thus, the content of protoporphyrin in circulating red blood cells 

represents what has accumulated during red blood cell maturation and consequently 

describes an effect that took place in the bone marrow, with a time lag of 

3-4 months (Sassa et.al., 1973). 

With increasing blood lead, there is a rapid exponential increase of 

protoporphyrin, with significant accumulations over baseline at PbB levels 

of approximately 15 pg/dl in infants and children (Roels et al., 1976; 

Piomelli et al., 1977, 1982; Hammond et al., 1984; Rabinowitz et al., 1985) 

and 25-30 pg/dl in adults (Roels et al ., 1975b; Grandjean and Lintrup, 

1978; Odone et al., 1979; Herber, 1980). The population dose-response 

relationship between EP and blood lead in children aged 10-15 years indicated 

that EP levels were significantly higher (> 2 standard deviations) than the 

reference mean in 50% of the children at a PbB level of 25 pg/dl (Roels. et al., 

1976). A study of 2004 children found that EP levels increased exponentially 

above a PbB of 18 pg/dl and that PbB levels of 29.9 and 35.2 pg/dl corresponded 

to EP elevations of more than 1 and 2 standard deviations, respectively, 

in 50% of the children studied (Piomelli et al., 1982). 

The health significance of EP or ZPP accumulation is attributed to 

the fact that it is evidence of impaired heme and hemoprotein formation in 

many tissues that results from lead's entry into mitochondria (CD, p. 12-46). 

Besides its role in the erythropoietic system in forming hemoglobin, heme is 

active in liver function, vitamin D metabolism, and the nervous system. 

These interactions, and lead's impact on them, are depicted back.in Figure 

7-1 and discussed below. 
P.74 

D-6 

a) Effects of Lead on Heme and Hemoglobin Synthesis and Erythrocytes 

Anemia is often the earliest manifestation of chronic and acute lead 

poisoning. It is defined as a hemoglobin concentration depressed below 

some clinically accepted level, usually about 9.5-11.0 grams of hemoglobin 

per dl blood. The symptoms of anemia in young children can include pallor, 

sallow complexion, fatigue, irritability, and decreased play activity. 

The anemia of lead poisoning is related to some combination of decreased 

heme and hemoglobin production and increased rate of red blood cell destruction. In addition to its inhibitory effects on heme synthesis, lead disturbs 

the biosynthesis of globin, the protein component of hemoglobin, disrupts 

enzymatic activities necessary for erythrocyte membrane stability and 

ultimately, cellular survival (e.g., pyrimidine nucleotidase, ATPase), and 

causes oxidative damage to the red blood cell membrane (White and Harvey, 

1972; Dresner et al., 1982; Gelman et al., 1978; Secchi et al., 1973; 

Valentine and Paglia, 1980; Angle and Mclntire, 1978; Moore et al., 1980; 

Levander et al., 1975). Although these effects on enzyme activity and 

globin synthesis are detectable at PbB levels as low as 10 and 20 pg/dl, 

respectively, their role, if any, in reduced hemoglobin synthesis and 

shortened erythrocyte survival at such levels is uncertain. 

In determining a PbB level of concern for anemia, it is important to 

distinguish the effects of lead from iron deficiency, which is prevalent in 

young children and could increase an individual's sensitivity to lead 

toxicity. Unfortunately, the available data do not provide sufficient 

information to separate this potentially confounding factor. In children 

with no obvious iron deficiencies, the incidence of anemia (defined as a 

hemoglobin concentration below 11 g/dl) rose sharply as the PbB levels 

increased from 37 to 100 pg/dl (Betts et al., 1973). At PbB levels below 

36 pg/dl, 14% of the children were anemic, compared to 36% with levels 
P.75 

D-7 

between 37 and 60 pg/dl. The criteria document cites a threshold PbB for 

anemia in children of 40 pg/dl (WHO, 1977) and 50 pg/dl in adults (CD, 

p. 12-28). However, until additional dose-response information on large 

groups of children is available, with appropriate controls for iron deficiency, 

this "threshold" should not be considered definitive. 

b) Heme Synthesis and Liver Function 

A major fraction of heme synthesized in the live r is used in the 

hemoprotein, cytochrome P-450. This hemoprotein is the terminal oxidase 

of the microsomal mixed function oxidase system that is involved in the 

metabolism of a variety of drugs and foreign toxins, as well as endogenous 

substrates such as steroid hormones (Granick et al. , 1978). Decreases in 

live r cytochrome P-450 content and in drug detoxification rates have been 

observed following acute and chronic lead administration in animals and in 

lead-poisoned children and occupationally-exposed adults (Scoppa et al. , 

1973; Alvares et al. , 1975, 1976; Meredith et al. , 1977; Chow and Cornish, 

1978). Lead-induced alterations and diminished cytochrome P-450 function 

are also believed responsible for the decreased excretion of 6 Beta-Hydroxycortisol (6, 3-0HF), a metabolite of Cortisol, in young children with 

moderate elevations of blood lead (46 pg/dl)(Saenger et al. , 1984). 

Because of children's vulnerability and exposure to drugs and foreign 

chemicals, and their high metabolic rates, these findings suggest that 

in the absence of conclusive data i t should be assumed that any indication of 

significantl y altered heme biosynthesis (e.g. , elevated EP) may also indicate 

a possible inhibition of liver detoxification function. 

c) Heme and Vitamin D Metabolism 

Renal 1-hydroxylase, another heme-requiring cytochrome P-450 mediated 

mitochondrial enzyme system, converts 25-hydroxyvitamin D (which is formed 

in the live r from vitamin D) to the hormonal metabolite 1 , 25-dihydroxy-
P.76 

D-8 

vitamin D (1,25-(0H)2 D) in the kidney. 1,25-(0H)2 D is the major active 

form of vitamin D in: 1) orchestrating the differentiation and turnover of 

cells in bone mineralization (CD, p. 12-41); 2) stimulating intestinal 

absorption of calcium and phosphorous (Sorell et al., 1977; Rosen et al., 

1980); 3) maintaining extra- and intra-cellular calcium homeostasis essential 

for cellular integrity and function (including responses to hormonal and 

electrical stimuli, modulation of cyclic nucleotide metabolism, and regulation 

of several enzyme systems) (Cheung, 1980; Rasmussen and Waisman, 1983; Rosen 

and Chesney, 1983; Rosen, 1983); 4) mediating the activation of various 

immunoregulatory processes (Provvedini et al., 1983; Bhalla et al., 1983; 

Tsoukas et al., 1984); and 5) mediating pancreatic function and insulin 

secretion (Clark et al., 1981; Kadowski and Norman, 1984a,b). 

In addition to its reliance upon heme, the biosynthesis of the vitamin 

D hormone is controlled largely by the functional integrity of the 

renal mitochondria, by the ionic (calcium, phosphorus) environment of the 

exracellular fluid, and by the active uptake of calcium by mitochondria 

(CD, p.12-38). Given lead's toxic effects on mitochondria, cellular 

energetics, and cytochrome P-450 function, and the fact that ferrochelatase 

activity in kidneys is inhibited by lead just as it is in red blood cells 

(Fowler et al., 1980), it is not surprising that lowered 1,25-(0H)2 D 

levels occur at PbB levels corresponding to those associated with the onset 

of EP accumulation in erythropoietic tissue. For example, a strong negative 

correlation between children 1,25-(OH)2D and PbB levels was found over a 

range of 12-120 pg/dl (Rosen et al., 1980). In children with PbB levels 

over 33 pg/dl, the reductions in 1,25-(0H)2 D were comparable to those 

observed in children with severe renal insufficiency lacking two-thirds of 

normal renal function, as well as in those children with a variety of in-borne 

metabolic disorders such as vitamin D-dependent rickets, oxalosis, and 
P.77 

D-9 

hypoparathyroidism (Rosen and Chesney, 1983; Chesney et al., 1983). 

Several other points should be made regarding the significance of 

lead-induced reductions in blood serum levels of 1,25-(0H)2 D: (1) Mahaffey 

et al. (1982) noted the possibility of a feedback mechanism by which leadinduced reductions in 1,25-(0H)2 D interfere with intestinal lead absorption, 

or that normal bone mineralization permits lead to be sequestered in bone. 

Recent experimental data in rats (Smith et al., 1981), however, indicate 

that: dietary intake of vitamin D does not affect blood lead concentration; 

low 1,25-(0H)2 D levels can inhibit calcium transport thereby enhancing 

lead absorption; and reduced 1,25-(0H)2 D levels do not protect target 

organs (e.g., kidney) by sequestering lead in bone. (2) Although chelation 

of children with elevated PbB levels results in a rapid (within 2 days) 

return to normal 1,25-(0H>2 D levels (Rosen et al., 1980), the vitamin D 

system's ability to recover only after lead levels are reduced does not 

necessarily imply that the system is operating as a normal biological 

feedback mechanism. (3) Decreased calcium levels and increased parathyroid 

hormone (PTH), along with impaired bone mineralization -- conditions that 

typically accompany severe vitamin D deficiency (as e.g., in rickets) --

are not evident in children with PbB levels below 62 pg/dl (Rosen et al., 

1980). However, PTH and serum calcium levels typically are normal even in 

children with stage I rickets; these changes are therefore not meaningful 

indicators of the signifiance of reduced 1 ,25-(OH)2 D in children (Rosen 

and Chesney, 1983). The fact that bone mineralization is impaired in 

vitamin D deficiency rickets but not in lead-induced 1,25-(0H)2 D deficiency 

is also not relevant since vitamin D deficient children may have normal or 

even elevated 1,25-(0H)2 D levels. 
P.78 

D-10 

The varied biological roles of 1,25-(0H)2 D in the body, including 

extra- and intracellular calcium homeostasis, cell differentiation/ 

maturation, immunoregulatory function, and pancreatic function, e.g., 

insulin secretion (Kadowski and Norman, 1984a,b,; Clark et al., 1981) are 

becoming increasingly evident. Impairment of these activities that results 

from lead's depression of circulating 1,25-(0H)2 D levels may underlie many 

of the diverse effects of lead. The criteria document concludes that "It 

appears likely that lead-induced reductions in heme underlie the effects 

seen in the vitamin D-endocrine system. This origin would account for the 

similarities in "thresholds" for the effects of lead on both EP accumulation 

and decreases in levels of 1,25-(0H)2 D. It also typifies a cascade of 

biological effects among various organ and physiological systems of the 

body, a cascade that can ultimtely encompass the entire organism" (CD, p. 

12-37) and "that impaired production of 1,25-(0H)2 D can have profound and 

pervasive effects on tissues and cells of diverse type and function throughout 

the body" (CD, p. 12-49). 

d) Heme Synthesis and the Nervous System 

The nervous system, both central and peripheral, is recognized'as a 

target of critical importance in the toxicity of lead. Behavioral, electrophysiological, morphological", and biochemical investigations have demonstrated 

alterations in brain function at relatively low levels of exposure, particularly 

when exposure occurs during early development. Mechanisms that explain the 

neurological effects of lead include (but are not limited to) direct alteration 

of sodium and calcium metabolism, inhibition of certain neuronal enzymes 

(Na, K-ATPase and adenyl cyclase), and a decrease in mitochondrial oxidative 

phosphorylation (Silbergeld et al., 1982). Other evidence suggests that 

some aspects of lead neurotoxicity may be mediated through its inhibition 

of heme synthesis by the following mechanisms: 
P.79 

D-11 

(i) Interference with neurotransmission by the heme precursor, ALA 

The excessive accumulation of ALA is believed to be linked to the 

clinical and biochemical similarities (e.g., paralysis, psychiatric disturbances, nerve demyelination) of lead intoxication and "porphyria", conditions 

in which elevated tissue concentrations of porphyrin precursors result from 

genetic or acquired deficiencies (Dagg et al., 1965; Moore et al., 1980). 

Excessive ALA levels in the brain may be responsible for some neurological 

dysfunctions associated with more mild lead exposure as well, since low 

levels of ALA in vitro can interfere at the neuromuscular junction or spinal 

cord with normal neurotransmission by y-aminobuityric acid (GABA), which 

ALA closely resembles (Nicol 1, 1976; Brennan and Cantrill, 1979; Silbergeld 

et al. 1980, 1982). Interference with GABA-ergic function by exposure to 

lead is consistent with such clinical and experimental signs of lead neurotoxicity as excitability, hyperactivity, hyperreactivity, and in severe 

cases, convulsions (Silbergeld and Lamon, 1980). 

(ii) Heme deficiency and altered neurochemical synthesis 

Litman and Correia (1983) have reported that lead treatment of rats 

was associated with an inhibition of the hepatic heme-requiring enzyme 

system, tryptophan pyrrolase, and resulted in significantly elevated brain 

levels of tryptophan, 5-hydroxyindoleacetic acid, and the neurotransmitter, 

serotonin. With infusion of heme, these increases were reversed. Elevated 

levels of tryptophan and its metabolites have been associated with human 

hepatic encephalopathy and with neurohistological and symptomatic changes 

seen in victims of acute porphyria attacks (e.g., alteration of brain neurons, 

axonal wasting, psychomotor disturbances) (Litman and Correia, 1983). It 

remains to be resolved, however, whether changes in this heme-dependent 

enzyme system alone can account for observed low-level lead neurotoxicity. 
P.80 

D-12 

(iii) Impairment of heme availability in neural tissue 

Heme biosynthesis appears to be inhibited in nervous system tissues at 

dose ranges comparable to those which are toxic in erythroid and liver 

cells (Whetsell et al., 1978; Sassa et al., 1979). Co-administration of 

heme and lead prevented most of the neuro-morphological effects caused by lead 

alone, namely destruction of myelin and Schwann cells and structural alterations 

of neurons (Whetsell and Kappas, 1981; Whetsell et al., 1984). These 

results are suggestive of heme's possible role in neurotoxicity, but again, 

firm conclusions must await further research, 

(iv) Impairment of cytochrome function in brain energy metabolism 

Another possible heme-mediated mechanism of lead neurotoxicity is 

suggested by findings that production and operation of the electron transport 

cytochrome C respiratory chain in the developing cerebral cortex are impaired 

when neonatal rats are chronically exposed to low levels of lead (Holtzman 

and Shen Hsu, 1976; Bull et al., 1979). Disruption of energy metabolism 

has been implicated in developmental delays in the metabolically active 

nervous system of young animals exposed to relatively low levels of lead 

(McCauley et al., 1979; Crofton et al., 1980). 

These linkages between the biochemical effects of lead on heme synthesis 

and neurological function are primarily based on animal or in vitro 

experimental data. As such, it is difficult at this time to determine a 

lead exposure level of concern for heme-related neurological impairments in 

humans. Nevertheless, the common biochemical processes operating across 

neurological and hematological systems in mammalian species suggest that 

the abnormalities in heme synthesis caused by low level lead exposure in 

humans may also indicate some risk of neurobehavioral impairments. 
P.81 

D-13 

2. Neurological Effects of Lead 

a) Acute Effects and Peripheral Nerve Damage 

The effects of lead on the nervous system are both structural and 

functional, involving various regions of the brain and spinal cord (i.e., the 

central nervous system) as well as the motor and sensory nerves leading to 

specific areas of the body (i.e., the peripheral nervous system). These 

effects can result in deterioration of intellectual, sensory, neuromuscular, 

and/or psychological functions. 

Acute encephalopathy (degenerative brain disease) is the most severe 

consequence of lead intoxication. Early features of the syndrome include 

lethargy, sporadic vomiting, irritability, loss of appetite, dizziness, 

poor attention span, muscular tremor, and memory loss. These signs can 

abruptly progress to delirium, convulsions, coma, and ultimately death 

(Cumings et al., 1959). Acute encephalopathy in adults usually is manifested 

at PbB levels of approximately 100-120 pg/dl (Chisolm and Harrison, 1956; 

Chisolm, 1965); scattered evidence (Gant et al., 1938; Smith et al ; 

1938; Bradley et al., 1956; Bradley and Baumgartner, 1958; Cumings, 1959; 

Rummo et al., 1979) suggests that this syndrome may be associated with PbB 

levels between 80 and 100 pg/dl in the most susceptible children (CD, p. 

12-62). 

Severe lead poisoning with or without encephalopathy has permanent 

effects on the behavior and intellectual functioning of children, even if 

subsequent lead exposure is minimized. Such sequelae range from mental 

retardation and cerebral palsy to sensorimotor deficits, short attention 

span, and optic atrophy (Byers and Lord, 1943; Chisolm and Harrison, 1956; 

Perlstein and Attala, 1966; Chisolm and Barltrop, 1979). 
P.82 

D-14 

While encephalopathy occurs primarily in children, peripheral nerve 

damage (neuropathy) due to high lead exposure is more commonly found in 

adults occupationally exposed to lead. Overt symptoms such as muscle 

tremor, palsy (e.g., "wrist drop") or weakness, muscle and joint pain, and 

gastrointestinal complaints have been observed in workers with PbB levels 

exceeding 40 ug/dl (Lilis et al., 1977; Spivey et al., 1979; Baker et 

al., 1979; Haenninen et al., 1979; Zimmerman-Tansella et al., 1983). Small 

reductions in nerve conduction velocities have been observed in some apparently 

asymptomatic workers with PbB levels as low as 30-50 ug/dl (Seppalainen 

et al., 1975, 1979; Araki and Honma, 1976; Melgaard et al., 1976; Ashby, 

1980; Bordo et al., 1982; Johnson et al., 1980; Seppalainen and Hernberg, 

1980, 1982; Singer et al., 1983; Triebig and Nottbohm, 1983). These observations were primarily on peripheral arm nerves that are responsible for the 

conduction of tactile and positional information, and information about 

painful stimuli and temperature. 

Overt, lead induced peripheral neuropathy has been documented in children 

with PbB levels above 60 pg/dl (Erenberg et al., 1974), and in some cases 

possibly as low as 40 yg/dl (CD, p. 12-95). Although more subtle signs 

of possible advancing neuropathy (i.e., slowed nerve conduction velocities) 

have been observed in children across a wide range of increasing PbB levels", 

(Landrigan et al., 1976), no clear threshold for abnormal function can be 

determined from the available data. 

In interpreting the effects of lead on the peripheral nervous system, 

it is important to note that: 1) Because these are chronic effects and 

PbB levels do not accurately reflect the long-term accumulation of body 

lead, it has not been determined if peak exposures prior to the time of 

study are responsible for the dysfunction, or the length of time that PbB 
P.83 

D-.15 

must remain above a certain level to cause impairment; 2) The range of 

nerve conduction velocities in humans is great, even when measured by a 

single investigator and, in almost all studies, most velocities among 

individuals are well within the range of normal values (although a statistical 

reduction in a population does indicate the need for reducing lead exposure; 

Seppalainen et al., 1975); and 3) Because peripheral nerves are able to 

regenerate, there is some dispute as to whether the observations of slowed 

nerve conduction velocities reflect mild, reversible impacts of lead (Buchtal 

and Behse, 1981) or are early warning signals of progressively more serious 

peripheral neuropathies that are important in the diagnosis of otherwise 

unrecognized toxic lead effects (Feldman et al., 1977; Seppalainen and 

Hernberg, 1980). 

The criteria document concludes "nevertheless it is clear that these 

effects represent departures from normal neurologic functioning and their 

potential relationship to other more serious effects argues for prudence in 

interpreting their potential health significance." (CD, p. 12-61) 

b) Effects Associated with Chronic Low-Level Exposures 

Besides the severe pathophysiological changes observed in the 

central nervous system associated with childhood lead intoxication, various 

maladaptive behaviors, neuropsychological deficits, and neuro-anatomical 

changes may be associated with chronic exposures to relatively low concentrations 

of lead. Below is a summary of the numerous biochemical, morphological, 

and functional effects of lead at low dosages and exposures that have been 

found in developing nervous systems. No single mechanism appears 

sufficient to account for the diverse effects of lead on neurological 

function, and it is more likely that lead acts at several cellular and 

sub-cellular sites. Although neurochemical changes may preceed observable 
P.84 

D-16 

effects on electrophysiology, morphology, and behavior in terms of dose, 

they are not separate from functional changes at higher levels. In those 

systems that have been examined pharmacologically in vitro (e.g., inhibition 

of adenyl cyclase, acetylcholine release, and Na,K-ATPase), a continuous 

dose-response relationship is suggested, best fitted by smooth curves with 

either no threshold or thresholds in the nanomolar range (Silbergeld, 1983). 

It should be noted that the findings from in vitro or animal studies 

cannot be directly extrapolated to estimate PbB levels associated with 

changes in pediatric neurological functions because: a) the relatively 

short lifespans of experimental animals alters the relationship between 

dose and duration assumed for humans; b) significant species differences 

exist for absorption, retention, and internal compartmentalization of lead; 

and c) with some exceptions, the measurements of neurotoxicity are not 

comparable to those possible in studies of children (Silbergeld and Goldberg, 

1980; Winneke et al., 1982b). However, in assessing the more overt effects 

reviewed in the next section, it is important to note this continuum of 

lead neurotoxicity starting with biochemical changes at the lowest observed 

dose levels. 

1) Brain Development 

Lead readily enters the brain and appears to be selectively deposited 

in the hippocampus and cortex as well as in non-neuronal elements (e.g., 

glial cells, endothelial cells of brain capillaries) that are important in 

the maintenance of "blood-brain barrier" functions (Fjerdingstad et al., 

1974; Grandjean, 1978; Stumpf et al., 1980). Once deposited, lead is 

retained in the brain for long periods of time even after external exposure 

ceases and PbB levels decline (Mykkanen et al., 1979; Goldstein et al., 

1974). These spatial and temporal patterns of brain lead accumulation 
P.85 

D-17 

correspond to the following neurobehavioral and morphologic abnormalities 

associated with lead exposure: 1) pathologic studies of exposed animals 

and encephalopathy humans that indicate changes of a primarily vascular 

(e.g., endothelial and glial cell) nature (Michaelson and Sauerhoff, 1974); 

2) animal studies that show effects on neuronal populations in the hippocampus 

and cortex and behavioral changes indicative of hippocampal and cerebellar 

dysfunction (Campbell et al., 1982; Petit and Alfano, 1979; Bushnell and 

Bowman, 1979); and most importantly 3) electro-physiological and behavioral 

changes associated with lead exposure measured in young animals and children 

that persist long after exposure is reduced or ceases (Brown, 1975; Otto et 

al., 1982). 

The sensitivity of the brain during the period of maximal brain growth 

and differentiation in the first 2 years of life tends to magnify the 

severity of the long-term consequences of any toxin encountered during that 

period (Dobbing, 1974). The immaturity of specific brain tissues (i.e., 

hippocampus, cerebellum and neocortex) at birth and their relatively late 

development suggests that post-natal lead exposure could interfere with 

mitosis, cellular migration, differentiation of dendritic and axonal 

processes, synaptogenesis, and myelin production, as well as exerting 

biochemical and cytotoxic effects (Campbell et al., 1982). While the 

developing nervous system may possess considerable reserve for functional 

compensation (involving plasticity, regeneration, and redundancy of neural 

pathways), specific processes affected by lead apparently may not be 

reversed, either because lead is not removed from brain cells (Silbergeld, 

1983) or because of interruption or damage to neurostructural components 

undergoing rapid development at the time of the lead insult. 
P.86 

D-18 

Rat pups exposed to low levels of lead during the pre-natal or neonatal 

period show retarded development in cerebral energy metabolic pathways, 

delayed cerebral cortex synaptogenesis, and reductions in hippocampal 

morphometric, dendritic, and axonal development (Bull et al., 1979, 1983; 

McCauley et al., 1979, 1982; Petit and Alfano, 1979; Alfano and Petit, 

1982; Petit and LeBoutillier, 1979; Campbell et al., 1982). These biochemical 

and morphological disruptions are paralleled by delays in the development 

of exploratory and locomotor activity, and by learning and behavioral 

deficits in young, lead-exposed animals (Bull et al., 1979, 1983; McCauley 

et al., 1979, 1982; Brown, 1975, Overmann, 1977; Bushnell and Bowman, 1979; 

Rice and Wille.s, 1979; Petit et al, 1983). 

The effects of in utero or post-natal lead exposures on human infant 

neurological development have begun to be investigated. Mentally retarded 

children in Scotland were more likely by a factor of 1.7 to come from homes 

in which high levels of lead in drinking water (> 800 ppm) were present 

during pregnancy compared to controls (Beattie et al., 1975). PbB levels 

in a sample of these children at 2 weeks of age were 25.8 +_ 8.9 pg/dl 

compared to 20.9 +_ 7.9 yg/dl in normal children (Moore et al., 1977). 

Although these are provocative findings, their quantitative value is uncertain 

given that the children were limited to those known to health care services 

(and hence not necessarily representative), the matching was imperfect, and 

the PbB levels were available for only about 50% of the children. 

Preliminary results from recently initiated prospective studies suggest 

that low to moderate lead exposure (mean PbB => 15 yg/dl) during the first 

two years of life may have a small impact on early sensorimotor and mental 

development (Bellinger et al., 1984; Dietrich et al., 1984). Assessment of 
P.87 

D-19 

the medical significance and persistence of these effects, if any, must 

await follow-up testing and replications from other longitudinal studies. 

2) Motor Coordination and Reflexes 

Pre- and post-natally lead-exposed rats tend to show developmental 

delays in their ability to orient properly and respond to selected reflexive 

stimuli (Overmann, 1977; Overmann et al., 1979, 1981; Grant et al., 1980). 

Impaired performance was observed in rats with PbB levels as low as 35 yg/dl 

at 11 days of age although no significant effects have been found at higher 

exposures in some studies using somewhat different measures of motor coordination and reflexes (Overmann et al., 1979; Zenick et al., 1979; Grant et 

al., 1980). These contrasting results can probably be attributed to differences 

in body weight, age at testing, and in the test apparatus and procedures 

(Zenick et al., 1979). 

Lead-induced abnormalities in motor ability may be linked to preferential 

concentration of lead in the cerebellum where posture and movement is 

regulated, or to lead's damaging effects on peripheral nerves and at the 

neuromuscular junction (Cooper and Manalis, 1974; Silbergeld et al., 1974). 

Small deficits in perceptual motor integration and fine motor 

coordination have been reported in children with PbB levels of 50-60 yg/dl, 

and possibly as low as 30-40 yg/dl (de la Burde and Choate, 1972, 1975; 

Landrigan et al., 1975; McBride et al., 1982; Needleman et al., 1979; 

Winneke et al., 1982a), or lower (Winneke et al., 1983). No significant 

lead-related deficits in psychomotor performance have been found at comparable 

PbB levels (i.e., 30-60 pg/dl) (Rummo, 1974; Rummo et al., 1979; Perino and 

Ernhart, 1974) and at PbB levels below 25 yg/dl (Winneke et al., 1984). 

No differences in fine motor scores were found in another study, although 

the mean PbB levels for the control group (26 yg/dl) may have been too 
P.88 

D-20 

high to detect any effect in the exposed group (PbB « 38 yg/dl) (Kotok, 

1972; Kotok et al., 1977). These conflicting results are analogous to 

those found in animal experiments in which somewhat different measures of 

motor coordination and reflexes were also used. Nevertheless, any deficits 

in perceptual motor and fine motor coordination that are, in fact, related to 

lead may be functional evidence of lead-induced decrements in motor nerve 

function. This has been noted in children and in adults who exhibit conduction 

deficits in distal-extremity nerves at PbB levels above 30 yg/dl (See 

Appendix D.2.a). Similarly, the findings of perceptual inaccuracies associated 

with lead exposure have been interpreted in terms of lead-induced attentional 

deficits which are discussed below (Winneke et al., 1983). 

3) Hyperactivity and Other Behavioral. Disorders 

Since Byers and Lord (1943) reported hyperactivity as a possible 

sequel for children who had recovered from lead poisoning, there has 

emerged a large and controversial data base concerning possible associations 

between lead and hyperactivity and other behavioral disturbances. Hyperactivity is a complex syndrome with respect to both cause and manifestation. Attention deficit disorder is generally thought to be the most 

salient manifestation of the condition (American Psychiatric Association, 

1980). This disorder occurs with and without hyperkinesis, which refers 

more to inappropriate and/or random activity than it does to an increase in 

activity, although the latter is sometimes seen (David et al., 1983). 

Other symptoms frequently present are impulsivity, low frustration tolerance, 

hyperexcitability, and disturbances in conduct (Wender, 1971; David et al., 

1983). 

Inconclusive findings of hyperkinesis have been reported in neonatally 

lead-exposed rodents (CD, Table 12-2). Attempts to collate these data are 
P.89 

D-21 

hampered by variability in the species, dose of lead, length and route of 

exposure, age, the methodology for activity testing and the presence of 

growth retardation. It has been proposed that a) the apparently discrepant 

findings on hyperkinesia are consistent with an explanation in terms of 

lead-induced, situation-specific, emotional or behavioral over-reactivity 

rather than hyperactivity per se (Hastings et al., 1977; Winneke et al., 

1982b; Kishi et al., 1983); b) these behavioral disturbances are consistent 

with previously described disruptions in hippocampal morphology and function 

(Petit et al., 1983); and c) these behavioral effects may contribute to 

learning deficits observed in lead-exposed animals (see Appendix D.2(b)5). 

Despite these interesting analogies between some of the changes in 

developmental animal behavior and hyperactive abnormalities, it would be 

premature to extrapolate from simple animal models to this complex clinical 

syndrome in children. Multiple etiologic factors including genetic influences, 

perinatal complications, covert cerebral insult, irregular brain maturation, 

maldevelopment and perhaps, most importantly, psychosocial factors can play 

a role in hyperactivity (David et al., 1983). Some studies that have 

attempted to control for these etiological factors and pica (which 

may be a consequence rather than a cause of hyperactivity) have found 

consistently higher lead levels in hyperactive children (Baloh et al., 

1975; David et al., 1976; Gittleman and Eskenazi, 1983), while other studies 

have not (Rummo, 1974; Mi 1ar et al., 1981). Because of methodological 

limitations, conclusions from these studies are also limited. 

In a more carefully controlled study, David et al. (1983) found that 

reductions in hyperactive children's PbB levels (from 29.3 to 19.5 yg/dl) 

as a result of chelation therapy with penicillamine were associated with 

marked symptomatic and behavioral improvements, as assessed by teachers, 
P.90 

D-22 

parents, and treating physicians. Hyperactive children given a therapeutic 

drug to treat the syndrome, but whose PbB levels remained approximately the 

same, showed some similar improvements while children given a placebo 

exhibited no significant changes in behavior ratings or PbB levels. 

The criteria document concludes that the above data are at best 

qualitatively suggestive and that if lead is indeed causally involved in 

the etiology or exacerbation of the behavioral abnormalities associated 

with hyperactivity, it is currently impossible to state with confidence 

the levels, durations or critical periods of lead exposure that may have 

been important (CD, p. 12-89). 

There is somewhat more convincing evidence that low PbB levels may 

contribute to some other behavioral disorders such as attentional deficits 

and distractibility in essentially normal children not diagnosed as hyperactive. Several analyses of classroom behavior have failed to adequately 

account for the influence of social class although they have produced 

consistent dose-response relationships in which teachers' ratings on 

several behavioral measures (e.g., "distractability", "not persistent", 

low overall functioning) increase parallel with tooth and PbB levels 

(de la Burde and Choate, 1972; Needleman et al., 1979; Yule et al., 1984). 

As is the case for several other general population studies (Landrigan et 

al., 1975; Winneke et al., 1983), hyperactivity was noted in very few 

children and was generally not associated with lead levels. After adjusting 

for socio-economic and other potentially confounding factors, behavioral 

and attentional deficits as rated by teachers (e.g., disordered classroom 

activity, restless, easily distracted, not persistent, does not follow 

directions, low overall functioning) were significantly associated with 

children's tooth and PbB levels (Winneke et al., 1983). The criteria document 
P.91 

D-23 

has interpreted this study, which also assessed lead-induced deficits in IQ 

and other psychometric tests, as showing overall neurobehavioral deficits 

at PbB levels possibly below 30 pg/dl (Winneke et al., 1983). 

In addition, lead levels in young children have been consistently 

associated, following appropriate adjustments, with deficits in reaction time 

under varying intervals, which is an index of attentiveness (Needleman et 

al., 1979; Winneke et al., 1983; Yule and Landsdown, 1983; Hunter et al., 

1983), and with reaction behavior (Winneke et al., 1984). The criteria 

document concludes that these findings appear to argue for probable effects 

of lead on attention and vigilance functions at PbB levels extending below 

30 pg/dl, and possibly, down to as low as 15-20 pg/dl (CD, p. 12-84). 

4) Auditory and Language Processing 

Central nervous system damage caused by severe childhood lead, 

poisoning is often associated with motor-speech and language disorders (Byers 

and Lord, 1943; Mel 1ins and Jenkins, 1955). There is conflicting evidence on 

whether subtle cerebral injury associated with chronic low-level lead absorption 

is manifested in impaired verbal behavior and auditory processing. Several 

studies have found no statistically significant lead-related differences on 

verbal subtests of standardized intelligence tests in children with PbB levels 

across a range from below 10 to above 60 pg/dl (de la Burde and Choate, 

1975; Landrigan et al., 1975; Kotok et al., 1977; Yule and Landsdown, 1983; 

Yule et al., 1984; Smith et al., 1983; Winneke et al., 1982a, 1983, 1984), 

while other studies have (Kotok, 1972; Rummo et al., 1979; Needleman et 

al., 1979; Yule et al., 1981). Significant associations, however, have been 

detected between children's lead levels (possibly as low as 30-50 pg/dl 

PbB) and a more extensive battery of measures, including motor-speech 

behaviors, language comprehension, formulation behaviors (Needleman et 
P.92 

D-24 

al., 1979; 1984) and auditory processing tasks (de la Burde and Choate, 

1975; Needleman et al., 1979). In addition to more specific measures of 

language and auditory function, these findings of lead-associated decrements 

may be attributable to samples drawn from among children with relatively 

early exposures to lead. 

Although no conclusions can be drawn from these findings, it is clear 

that further research on low level lead effects in children should include 

sensitive measures of motor-speech behaviors and communication impairments. 

Because maturation of the auditory cortex, which plays a vital role in 

language processing, and the onset of competence in speech and language occurs 

within the second year of life (Shaheen, 1984), such research should include 

assessments of the effects of lead absorption in children prior to their 

second birthdays. 

5) Cognitive Function 

In addition to deficits in behavioral functions, fine motor control, 

and auditory, language and speech development, there is evidence that low 

levels of lead may be associated with effects on some complex cognitive 

functions including learning, visual-perception skills, and IQ scores. In 

studies not confounded by nutritional or litter effects (a common problem 

in behavioral assays), rats exposed to lead in utero and/or through 

early development, resulting in PbB levels below 30 yg/dl and as low as 

20 yg/dl, display alterations in learning task performances (visual 

discrimination, shock avoidance, operant conditioning) (Winneke et al., 

1977, 1982b; Cory-Slechta and Thompson, 1979; Gross-Selbeck and Gross-Selbeck, 

1981). Monkeys exposed for one year after birth to achieve PbB levels 

between 30 and 50 yg/dl were significantly retarded in their ability to 

learn spatial and discrimination tasks (Bushnell and Bowman, 1979) and in 
P.93 

0-25 

their ability to alter their behavior under changed learning conditions 

(Rice and Willes, 1979). After lead dosing ceased, the lead treated monkeys 

at 2-3 years of age (PbB * 20 yg/dl) had higher response rates than 

controls to reinforced stimuli (Rice et al., 1979), and deficits in spatial 

memory persisted in these monkeys at 4-5 years of age when PbB levels had 

stabilized at 5 yg/dl (Levin and Bowman, 1983). PbB levels are presented 

for comparative purposes only and should not be extrapolated to human doseresponse relationships. 

In considering these effects, it should be noted that performance in a 

learning task is based on a number of functional processes, such as motor 

functions, emotional-motivational conditions, sensory functions, and cognitive 

functions (namely memory and/or learning processes, i.e., the formation and 

retention of stimulus-response associations) (Bornschein et al., 1980; Winneke 

et al., 1982b). 

It has been suggested that the above findings, which include "improved" 

performance in lead-treated animals on some learned tasks where success 

was measured by rapid response, indicate an underlying tendency to respond 

excessively or a behavioral "over-reactivity," whether or not such response 

is appropriate (Winneke et al., 1982b). This interpretation corresponds to 

some extent to lead-induced increases in locomotor activity and responsedisinhibition (Overmann, 1977; Winneke et al., 1977; Schlipkoter and Winneke, 

1980). Taken together, these data indicate that lead exposure during early 

development is disruptive in attention-demanding, difficult discrimination 

learning and complex neuropsychological performance and reduces responsiveness 

to contingencies in the environment, but this exposure facilitates active 

avoidance and other simple learning tasks (Overmann, 1977; Winneke et al., 

1982b). Although these results cannot be quantitatively extrapolated to 
P.94 

D-26 

children, they are in agreement with findings from recent studies that lead 

at low doses may be associated with a spectrum of alterations in children's 

behavioral, academic, and possibly intellectual development (see below). 

These studies on children have attracted controversy because of difficulties 

associated with attributing subtle deficits in child development to lead exposure rather than to effects due to genetics, nutrition, medical history, 

access to education, and parental and social influences, all of which interact 

in potentially complex ways to mold an individual (Pearson and Dietrich, 

1985). Untangling these different sources of behavioral variance is complicated 

by the necessary focus on children from lower socioeconomic areas where lead 

exposure is elevated and learning and caregiving conditions often are not 

ideal. 

Other difficulties encountered in the conduct and interpretation of 

childhood lead studies include: 1) accurately classifying exposure since PbB 

is an index of recent, but not necessarily historical, lead exposure, and 

because the relationship between tooth and PbB levels is uncertain; 2) inappropriate measurement covariates (e.g., social class as an index of 

parental care and intellectual stimulation) that can bias regression analyses; 

3) incomplete assessment of complex behavioral and intellectual processes; 

and 4) possible non-representativeness of study samples since most studies 

relied on information from either pre-selected clinic groups along with a 

selected "match" sample, or volunteers from the general population who may be 

more altruistic, interested, or better informed (Smith et al., 1983). 

Based on five methodological criteria (adequate markers of lead exposure, 

sensitive measures of neurobehavioral function, appropriate subject selection, 

control of confounding covariates, and appropriate statistical analysis), the 

criteria document has identified a group of neurobehavioral studies that 

"were conducted rigorously enough to warrant at least some consideration 

here" (CD, p. 12-65). 
P.95 

D-27 

As with other parameters of neuropsychological performance, there 

have been mixed findings regarding lead's association with children's 

scores on standardized IQ tests, which measure some combination of literacy, 

information, academic capacity, and intelligence (Flynn, 1984). Several 

well-controlled studies have found effects that are clearly statistically 

significant whereas others have found "non-significant" but borderline 

effects. It is important to note that: 1) the definition of "statistical 

significance" (p < 0.05) is somewhat arbitrary and should not be used to 

totally exclude results that may have important public health implications; 

and 2) given the likely subtle nature of the behavioral or neural effects 

probable at low levels of lead exposure, the differential maturation patterns 

and sensitivities among different brain processes, and the many other factors 

that play a larger role in an individual's developmental trajectory, one 

would not expect to find striking differences in every study, especially in 

those that use standardized but non-specific measures of intelligence or 

academic capacity. 

The general indication from the better investigations is that PbB levels 

persistently elevated in the range of 50-70 yg/dl tend to be associated, on 

average, with about a 5 point reduction in IQ, even among asymptomatic children 

and after controlling for potentially confounding variables (de la Burde and 

Choate, 1972, 1975; Rummo, 1974; Rummo et al., 1979). A 5 point decrease in 

children's average IQ score, given the normal curve of distribution of 

intelligence, would be associated with a doubling in the number of children 

with IQ's below 70 (the level used to define mental retardation), as well as 

a reduction in the number of children with IQ's above 125 (Rutter, 1980). 

Thus, while any individual child's IQ score may fluctuate over time, the 

implications of a 5 point average deficit among children are serious. 
P.96 

DT,28 

Considerable uncertainty exists regarding lead's impact on IQ scores of 

children with PbB levels below 40 pg/dl. This uncertainty largely stems from 

the complex interaction between lead exposure over time, social factors, and 

intelligence scores, and from the statistical and methodological limitations 

of cross-sectional studies to untangle these variables, and the range of 

interpretations that result from these studies. For example, Ernhart 

(1983, 1984) reanalyzed previously-published data on a group of children 

whose average PbB level dropped from 35.2 to 26.9 pg/dl over 5 years 

(Perino and Ernhart, 1974; Ernhart et al., 1981) and found that after 

partialling out the effects of sex, parental IQ, and parental education (but 

not socio-economic status), the proportion of variance explained by lead was 

no greater than 5% on any one of the IQ measures. With the exception of General 

Cognitive Index and Verbal Scale scores, the effects of early lead exposure 

on IQ scores appeared to be neither statistically significant nor persistent 

throughout childhood. It is possible, as with other studies, that by controlling for one variable such as parental IQ, which may be affected by lead 

exposure, the effects of lead on children's IQ is diminished. Ernhart (1983) 

concluded that although these data do not support an inference for an 

association between neuropsychologic deficits and lead exposures at the 

levels experienced by the children in this study, the rather low statistical 

power of the reanalyses does not allow for a definitive conclusion of "noeffect", either. Nevertheless, the results from these analyses are reasonably 

consistent with those from other investigators; namely that PbB levels above 

30 pg/dl, compared to lower levels, show a small, but significant association 

with some measures of IQ after controlling for confounding variables. 

The criteria document concluded from the Needleman et al. (1979) study 

and subsequent re-analyses (Needleman, 1984) that, after controlling for 
P.97 

D-29 

confounding variables including pica, average IQ decrements of about 4 

points appear to be associated with PbB levels in the 30-50 pg/dl range 

(CD, p. 12-74 to 12-80). Needleman et al. (1982) calculated that a 4 point 

decrement in the mean IQ of a normal population distribution would be associated 

with a three-fold increase in the number of children with severe deficits (IQ 

< 80) along with a 5% reduction in the number of children who attain superior 

function (IQ > 125). It is of interest to note that two pilot studies 

(Yule et al., 1981; Winneke et al., 1982a) that included children with 

PbB levels below 30-35 pg/dl (Rutter, 1983) living near lead smelters in 

Europe found IQ deficits (4.5 to 7 points) similar to those observed by 

Needleman et al. (1979) between high and low exposure groups after 

correction for confounding variables. However, the relatively crude 

controls for social variables provided in these latter two pilot studies 

prevent conclusive interpretation of the observed associations (CD, p. 

12-86). 

Studies of European children with lower lead exposures (mean PbB « 8-

15 pg/dl) have generally found only 1-2 point, and statistically non-significant differences in various IQ scores at PbB levels in the 15-30 pg/dl 

range after controlling for confounding variables (Smith et al., 1983; Harvey 

et al., 1983, 1984; Yule et al., 1983; Yule and Landsdown, 1983; Winneke et 

al., 1983, 1984). Smith et al. (1983) commented that if differences exist in 

neuropsychological performance attributable to lead at the levels they studied 

(<25 pg/dl), then the sensitivity of psychological tests and other currently 

available measures and statistical procedures do not allow these differences 

to be detected with any degree of certainty. 

An important finding from several of these studies that tested for 

interactive effects (Yule and Landsdown, 1983; Winneke et al., 1983; 

Harvey et al., 1983) was that neurobehavioral deficits associated with 
P.98 

DT3 0 

lead were enhanced in, or even largely confined to, socially disadvantaged 

children compared to those from more middle class backgrounds. These findings 

suggest that low level lead exposure, in combination with other factors 

associated with low socio-economic status (e.g., undernutrition) may 

predispose a child to psychological impairment. Further research is 

needed to investigate the possibility that the effects of low levels of 

lead (PbB < 30 pg/dl) on IQ are due, not to some "pure" form of permanent 

damage to the brain, as much as to the effects of lead as part of a more 

complex set of interacting influences including social and nutritional 

factors. 

5) Electrophysiological Effects 

As discussed earlier, in addition to its varied effects on neuronal 

development and chemically-mediated synaptic transmission, lead impairs 

peripheral nerve conduction velocities, at levels possibly as low as 

30 pg/dl (Appendix D.2.a). Similarly, lead exposure affects brain 

morphology and metabolism, interferes with neurotransmission in central 

nervous system tissue (e.g., cerebellum, retina) (Palmer et al., 1981; 

Fox and Sillman, 1979; Sillman et al., 1982), and depresses conduction 

velocities in the visual pathways of rats accompanied by persistent 

decreases in visual acuity and spatial resolution (Fox et al., 1977; 

Cooper et al., 1980; Winneke, 1980; Impelman et al., 1982; Fox and Wright, 

1982). Consistent with these findings are those from neurological assessments 

of children and adult workers which provide consistent findings indicating 

that a wide range of lead levels are associated with impaired function in 

the visual-motor and auditory systems (Repko, 1979; Haenninen et al., 

1978; Needleman et al, 1979; Winneke et al., 1983). 
P.99 

D-31 

It has also been demonstrated that electrical activity in the brain 

itself, determined by electroencephalograms (EEG), is disrupted in animals 

and humans suffering from lead intoxication (Cooper et al., 1980). More 

subtle abnormalities in EEG patterns (increased delta/decreased alpha 

activity) were detected in a subset of children from the Needleman et al. 

(1979) study with high tooth lead levels (Burchfiel et al., 1980). The 

lower amounts of alpha activity in the high lead children (PbB levels 

» 30-50 pg/dl; CD, p. 12-92) might signify that brain maturation was 

somewhat delayed by lead since such activity tends to increase with age 

in children (Beningnus et al., 1981). 

The brain wave patterns (indexed by slow cortical potentials elicited 

by classical conditioning) of 1-6 year old children varied as a linear 

function of PbB (ranging from 6-59 pg/dl) with no evidence of a threshold, 

although the slope changed systematically with age (Otto et al., 1981). 

Slow wave voltage tended to be positive in children less than 5 years old 

and negative in children over 5 years. Neurophysiological evidence suggests 

that slow surface-positive potentials in very young children may reflect 

axodendritic inhibitory processes (Otto and Reiter, 1984). Rostron (1982) 

has speculated that these findings suggest a decrease in attentiveness with 

increased PbB levels, perhaps lending support to findings of greater 

distractability in children with elevated lead levels (Needleman et al., 

1979; Winneke et al., 1983; Yule et al., 1984). The relative amplitude of 

synchronized electrical activity between the left and right hemispheres of 

the brain varied as a cubic function of PbB levels in these children, 

with inflection points at 15 pg/dl and 40 pg/dl (Beningnus et al., 

1981). Increased synchrony and relative amplitude of the EEG at these 

points could indicate an increase in the amount of information being 
D-32 

processed and, perhaps, that an increased effort is required to assimilate 

this information (Rostron, 1982). 

In a subsample of these children assessed 2 years later, slow-wave 

voltage during sensory conditioning again varied linearly with PbB with no 

apparent threshold over a range of 11-39 yg/dl (Otto et al., 1982). This 

relationship was constant whether PbB levels from the initial or follow-up 

study were analyzed, suggesting a change that persisted over time despite 

a substantial decline in mean PbB from 32.5 to 21.1 yg/dl. In a five-year 

follow-up on a subset of the same children, significant associations were 

found between PbB levels and increased latencies in brainstem auditory 

evoked potentials (Otto et al., 1984). The authors stated that while the 

functional significance of slow wave changes associated with Pb exposure is 

uncertain, the slowing of nerve conduction in the auditory pathway has been 

unambiguously related to pathological lesions and non-specific demyelinating 

diseases such as multiple sclerosis; therefore the latter effects on brainstem 

auditory evoked potentials are clearly indicative of neurological impairment 

(Otto et al., 1984). 

Interpretation of these data must be tempered by uncertainties regarding: 

1) the clinical and functional significance of many of the electrophysiological 

measures used that are presently considered experimental; 2) the PbB 

levels actually associated with the observed effects; 3) several inconsistent 

correlations between PbB and derived EEG measures within the population 

over time; and 4) the representativeness of the data since only 43 children 

were initially studied, and 28 subsequently evaluated in the follow-up studies. 

Nevertheless, the criteria document concludes that these findings 

"provide clear evidence of altered CNS functioning associated with relatively 

low level lead exposure at PbB levels in the 15-30 yg/dl range, and