Appendix C to Subpart C of Part 197 - Medical Surveillance Guidelines for Benzene
46:7.0.1.5.30.3.75.18.3 : Appendix C
Appendix C to Subpart C of Part 197 - Medical Surveillance
Guidelines for Benzene I. Route of Entry
Inhalation; skin absorption.
II. Toxicology
Benzene is primarily an inhalation hazard. Systemic absorption
may cause depression of the hematopoietic system, pancytopenia,
aplastic anemia, and leukemia. Inhalation of high concentrations
may affect the functioning of the central nervous system.
Aspiration of small amounts of liquid benzene immediately causes
pulmonary edema and hemorrhage of pulmonary tissue. There is some
absorption through the skin. Absorption may be more rapid in the
case of abraded skin or if it is present in a mixture or as a
contaminant in solvents which are readily absorbed. The defatting
action of benzene may produce primary irritation due to repeated or
prolonged contact with the skin. High concentrations are irritating
to the eyes and the mucous membranes of the nose and respiratory
tract.
III. Signs and Symptoms
Direct skin contact with benzene may cause erythema. Repeated or
prolonged contact may result in drying, scaling dermatitis or
development of secondary skin infections. In addition, benzene is
absorbed through the skin. Local effects of benzene vapor or liquid
on the eye are slight. Only at very high concentrations is there
any smarting sensation in the eye. Inhalation of high
concentrations of benzene may have an initial stimulatory effect on
the central nervous system characterized by exhilaration, nervous
excitation, or giddiness, followed by a period of depression,
drowsiness, or fatigue. A sensation of tightness in the chest
accompanied by breathlessness may occur and ultimately the victim
may lose consciousness. Tremors, convulsions, and death may follow
from respiratory paralysis or circulatory collapse in a few minutes
to several hours following severe exposures.
The detrimental effect on the blood-forming system of prolonged
exposure to small quantities of benzene vapor is of extreme
importance. The hematopoietic system is the chief target for
benzene's toxic effects which are manifested by alterations in the
levels of formed elements in the peripheral blood. These effects
may occur at concentrations of benzene which may not cause
irritation of mucous membranes or any unpleasant sensory effects.
Early signs and symptoms of benzene morbidity are varied. Often,
they are not readily noticed and are non-specific. Complaints of
headache, dizziness, and loss of appetite may precede or follow
clinical signs. Rapid pulse and low blood pressure, in addition to
a physical appearance of anemia, may accompany a complaint of
shortness of breath and excessive tiredness. Bleeding from the
nose, gums, or mucous membranes and the development of purpuric
spots (small bruises) may occur as the condition progresses.
Clinical evidence of leukopenia, anemia, and thrombocytopenia,
singly or in combination, may be among the first signs.
Bone marrow may appear normal, aplastic, or hyperplastic and may
not, in all situations, correlate with peripheral blood forming
tissues. Because of variations in the susceptibility to benzene
morbidity, there is no “typical” blood picture. The onset of
effects of prolonged benzene exposure may be delayed for many
months or years after the actual exposure has ceased.
Identification or correlation with benzene exposure must be sought
out in the occupational history.
IV. Treatment of Acute Toxic Effects
Remove from exposure immediately. Make sure you are adequately
protected and do not risk being overcome by fumes. Give oxygen or
artificial resuscitation, if indicated. Flush eyes, wash skin if
contaminated, and remove all contaminated clothing. Symptoms of
intoxication may persist following severe exposures. Recovery from
mild exposures is usually rapid and complete.
V. Surveillance and Preventive Considerations
(a) General. The principal effects of benzene exposure
addressed in 46 CFR part 197, subpart C, appendix A, are
pathological changes in the hematopoietic system, reflected by
changes in the peripheral blood and manifested clinically as
pancytopenia, aplastic anemia, or leukemia. Consequently, the
medical surveillance program specified in 46 CFR 197.560 is
designed to observe, on a regular basis, blood indices for early
signs of these effects. Although early signs of leukemia are not
usually available, emerging diagnostic technology and innovative
regimes are making consistent surveillance for leukemia, as well as
other hematopoietic effects, more and more beneficial.
Initial and periodic medical examinations must be provided as
required in 46 CFR 197.560. There are special provisions for
medical tests in the event of hematologic abnormalities or
emergencies.
The blood values which require referral to a hematologist or
internist are noted in 46 CFR 197.560(d) (i), (ii), and (iii). That
section specifies that, if blood abnormalities persist, the
employee must be referred unless the physician has good reason to
believe that the referral is unnecessary. Examples of conditions
that might make a referral unnecessary despite abnormal blood
limits are iron or folate deficiency, menorrhagia, or blood loss
due to some unrelated medical abnormality.
Symptoms and signs of benzene toxicity can be non-specific. Only
a detailed history and appropriate investigative procedures will
enable a physician to rule out or confirm conditions that place the
employee at increased risk. To assist the examining physician with
regard to which laboratory tests are necessary and when to refer an
employee to the specialist, the following guidelines have been
established.
(b) Hematology Guidelines. A minimum battery of tests is
to be performed by strictly standardized methods.
(1) Red cell, white cell, platelet counts, white blood cell
differential, hematocrit, and red cell indices must be performed by
an accredited laboratory. The normal ranges for the red cell and
white cell counts are influenced by altitude, race, and sex and,
therefore, should be determined by an accredited laboratory in the
specific area where the tests are performed.
Either a decline from an absolute normal or from an individual's
base line to a subnormal value or a rise to a supra-normal value
are indicative of potential toxicity, particularly if all blood
parameters decline. The normal total white blood count is
approximately 7,200/mm 3 plus or minus 3,000. For cigarette
smokers, the white count may be higher and the upper range may be
2,000 cells higher than normal for the laboratory. In addition,
infection, allergies, and some drugs may raise the white cell
count. The normal platelet count is approximately 250,000 with a
range of 140,000 to 400,000. Counts outside this range should be
regarded as possible evidence of benzene toxicity.
Certain abnormalities found through routine screening are of
greater significance in the benzene-exposed worker and require
prompt consultation with a specialist, namely:
(i) Thrombocytopenia.
(ii) A trend of decreasing white cell, red cell, or platelet
indices in an individual over time is more worrisome than an
isolated abnormal finding at one test time. The importance of a
trend highlights the need to compare an individual's test results
to baseline, to previous periodic tests, or to both.
(iii) A constellation or pattern of abnormalities in the
different blood indices is of more significance than a single
abnormality. A low white count not associated with any
abnormalities in other cell indices may be a normal statistical
variation. Whereas, if the low white count is accompanied by
decreases in the platelet and/or red cell indices, such a pattern
is more likely to be associated with benzene toxicity and merits
thorough investigation.
Anemia, leukopenia, macrocytosis, or an abnormal differential
white blood cell count should alert the physician to investigate
further and to refer the patient if repeat tests confirm the
abnormalities. If routine screening detects an abnormality, the
follow-up tests which may be helpful in establishing the etiology
of the abnormality are the peripheral blood smear and the
reticulocyte count.
The extreme range of normal for reticulocytes is 0.4 to 2.5
percent of the red cells. The usual range is 0.5 to 1.2 percent of
the red cells. A decline in reticulocytes to levels of less than
0.4 percent is to be regarded as possible evidence of benzene
toxicity requiring accelerated surveillance (unless another
specific cause is found). An increase in reticulocyte levels to
above 2.5 percent also may be consistent with, but not
characteristic of, benzene toxicity.
(2) A careful examination of the peripheral blood smear is an
important diagnostic test. As with the reticulocyte count, the
smear should be with fresh uncoagulated blood obtained from a
needle tip following venipuncture or from a drop of earlobe blood
(capillary blood). If necessary, the smear may, under certain
limited conditions, be made from a blood sample anticoagulated with
EDTA (but never with oxalate or heparin). When the smear is to be
prepared from a specimen of venous blood which has been collected
by a commercial Vacutainer ® type tube containing neutral EDTA, the
smear should be made as soon as possible after the venesection. A
delay of up to 12 hours is permissible between the drawing of the
blood specimen into EDTA and the preparation of the smear if the
blood is stored at refrigerator (not freezing) temperature.
(3) The minimum mandatory observations to be made from the smear
are as follows:
(i) The differential white blood cell count.
(ii) Description of abnormalities in the appearance of red
cells.
(iii) Description of any abnormalities in the platelets.
(iv) A careful search must be made of every blood smear for
immature white cells such as band forms (in more than normal
proportion, i.e., over ten percent of the total differential
count), any number of metamyelocytes, myelocytes, or myeloblasts.
Any nucleate or multinucleated red blood cells should be reported.
Large “giant” platelets or fragments of megakaryocytes must be
recognized.
An increase in the proportion of band forms among the
neutrophilic granulocytes is an abnormality deserving special
mention. Such an increase may represent a change which should be
considered as an early warning of benzene toxicity in the absence
of other causative factors (most commonly infection). Likewise, the
appearance of metamyelocytes, in the absence of another probable
cause, is to be considered a possible indication of benzene-induced
toxicity.
An upward trend in the number of basophils, which normally do
not exceed about 2.0 percent of the total white cells, is to be
regarded as possible evidence of benzene toxicity. A rise in the
eosinophil count is less specific but may indicate toxicity if the
rise is above 6.0 percent of the total white count.
The normal range of monocytes is from 2.0 to 8.0 percent of the
total white count with an average of about 5.0 percent. About 20
percent of individuals reported to have mild but persisting
abnormalities caused by exposure to benzene show a persistent
monocytosis. The findings of a monocyte count which persists at
more than ten to 12 percent of the normal white cell count (when
the total count is normal) or persistence of an absolute monocyte
count in excess of 800/mm 3 should be regarded as a possible sign
of benzene-induced toxicity.
A less frequent but more serious indication of benzene toxicity
is the finding in the peripheral blood of the so-called “pseudo”
(or acquired) Pelger-Huet anomaly. In this anomaly, many, or
sometimes the majority, of the neutrophilic granulocytes possess
two round nuclear segments, or, less often, one or three round
segments, rather than three normally elongated segments. When this
anomaly is not hereditary, it is often, but not invariably,
predictive of subsequent leukemia. However, only about two percent
of patients who ultimately develop acute myelogenous leukemia show
the acquired Pelger-Huet anomaly. Other tests that can be
administered to investigate blood abnormalities are discussed
below. However, these tests should be undertaken by the
hematologist.
An uncommon sign, which cannot be detected from the smear but
can be elicited by a “sucrose water test” of peripheral blood, is
transient paroxysmal nocturnal hemoglobinuria (PNH). This sign may
first occur insidiously during a period of established aplastic
anemia and may be followed within one to a few years by the
appearance of rapidly fatal, acute myelogenous leukemia. Clinical
detection of PNH, which occurs in only one or two percent of those
destined to have acute myelogenous leukemia, may be difficult. If
the “sucrose water test” is positive, the somewhat more definitive
Ham test, also known as the acid-serum hemolysis test, may provide
confirmation.
(v) Individuals documented to have developed acute myelogenous
leukemia years after initial exposure to benzene may have
progressed through a preliminary phase of hematologic abnormality.
In some instances, pancytopenia (i.e., a lowering in the
counts of all circulating blood cells of bone marrow origin, but
not to the extent implied by the term “aplastic anemia”) preceded
leukemia for many years. Depression of a single blood cell type or
platelets may represent a harbinger of aplasia or leukemia. The
finding of two or more cytopenias or pancytopenia in a
benzene-exposed individual must be regarded as highly suspicious of
more advanced, although still reversible, toxicity. Pancytopenia
coupled with the appearance of immature cells (myelocytes,
myeloblasts, erythroblasts, etc.) with abnormal cells (pseudo
Pelger-Huet anomaly, atypical nuclear heterochromatin, etc.) or of
unexplained elevations of white blood cells must be regarded as
evidence of benzene overexposure, unless proved otherwise. Many
severely aplastic patients manifested the ominous finding of five
to ten percent myeloblasts in the marrow, occasional myeloblasts
and myelocytes in the blood, and 20 to 30 percent monocytes. It is
evident that isolated cytopenias, pancytopenias, and even aplastic
anemias induced by benzene may be reversible and complete recovery
has been reported on cessation of exposure. However, because any of
these abnormalities is serious, the employee must immediately be
removed from any possible exposure to benzene vapor. Certain tests
may substantiate the employee's prospects for progression or
regression. One such test would be an examination of the bone
marrow, but the decision to perform a bone marrow aspiration or
needle biopsy must be made by the hematologist.
The findings of basophilic stippling in circulating red blood
cells (usually found in one to five percent of red cells following
marrow injury) and detection in the bone marrow of what are termed
“ringed sideroblasts” must be taken seriously, as they have been
noted in recent years to be premonitory signs of subsequent
leukemia.
Recently peroxidase-staining of circulating or marrow neutrophil
granulocytes, employing benzidine dihydrochloride, have revealed
the disappearance of, or diminution in, peroxidase in a sizable
proportion of the granulocytes. This has been reported as an early
sign of leukemia. However, relatively few patients have been
studied to date. Granulocyte granules are normally strongly
peroxidase positive. A steady decline in leukocyte alkaline
phosphatase has also been reported as suggestive of early acute
leukemia. Exposure to benzene may cause an early rise in serum
iron, often but not always associated with a fall in the
reticulocyte count. Thus, serial measurements of serum iron levels
may provide a means of determining whether or not there is a trend
representing sustained suppression of erythropoiesis.
Measurement of serum iron and determination of peroxidase and of
alkaline phosphatase activity in peripheral granulocytes can be
performed in most pathology laboratories. Peroxidase and alkaline
phosphatase staining are usually undertaken when the index of
suspicion for leukemia is high.