[exim] defer (-46) / SMTP error 421 on replies

I have installed the Exim RPM (exim-4.67.32.fc7) on my Fedora 7 server
(2.6.22.1-41.fc7) and configured it to work with a smart host (with
authentication) at my ISP by modifying the exim.conf which was delivered
in the RPM.

This replaced a previous Exim 4 installation on a Red Hat 9 server which
worked without any problems in the same environment (same smart host, same
domains, same network).

There are some differences in the new configuration, which is why I didn't
just re-use the old configuration file. I added clamd and spamassassin as
well as TLS encryption, for example.

Most of the time, the new configuration works very well. However, I
sometimes have e-mail REPLIES getting stuck in the output queue. There is
always a log entry which looks something like the following when this
happens:

2007-09-16 06:01:37 1IWfFJ-0000sF-0B == <sender@???>
R=send_to_smart_host T=remote_smtp defer (-46): SMTP error from remote
mail server after end of data: host <my.smart.host> [<smart.host.ip>]: 421
<my.smart.host> Lost connection to [<my.firewall.ip>]

These entries are followed by retry entries as follows until Exim gives up
and the mail is returned to sender:

2007-09-16 06:56:36 1IWfFJ-0000sF-0B == <sender@???>
R=send_to_smart_host T=remote_smtp defer (-53): retry time not reached for
any host

This only happens for replies. If I make a new e-mail with the same
content (e.g. using Mac OS X Mail.app: Message -> Send Again) and the same
recipient, it is successfully sent.

I asked my ISP if they could tell me what they see in their logs in these
cases: they thought it could be a verification problem, but they couldn't
be sure and said my logs ought to contain more information.

Unfortunately I don't understand the information in the logs, and googling
and reading the docs hasn't led me to enlightenment.

I'd be very grateful for any insight you could share or tips on where I
should be looking to resolve this problem.

Regards
Steve